Compounds

ABSTRACT

The present invention relates to substituted sulfonamide compounds of the general formula (I), wherein P is sulfonamide or amide-substituted sulfonic acid, which compounds are potentially useful for the prophylaxis and treatment of medical conditions relating to obesity, type II diabetes and/or disorders of the central nervous system.

RELATED APPLICATIONS

This application claims priority to Swedish application number0102048-6, filed on Jun. 11, 2001, Swedish application number 0102386-0,filed on Jul. 3, 2001, and Swedish application number 0103437-0, filedon Oct. 16, 2001, the contents of which are incorporated herein byreference.

TECHNICAL FIELD

The present invention relates to substituted sulfonamide compounds, topharmaceutical compositions comprising these compounds, and to the useof the compounds for the prophylaxis and treatment of medical conditionsrelating to obesity, type II diabetes, and CNS disorders.

BACKGROUND ART

Obesity is a condition characterized by an increase in body fat contentresulting in excess body weight above accepted norms. Obesity is themost important nutritional disorder in the western world and representsa major health problem in all industrialized countries. This disorderleads to increased mortality due to increased incidences of diseasessuch as cardiovascular disease, digestive disease, respiratory disease,cancer and type II diabetes. Searching for compounds, which reduce bodyweight has been going on for many decades. One line of research has beenactivation of serotoninergic systems, either by direct activation ofserotonin receptor subtypes or by inhibiting serotonin reuptake. Theexact receptor subtype profile required is however not known.

Serotonin (5-hydroxytryptamine or 5-HT), a key transmitter of theperipheral and central nervous system, modulates a wide range ofphysiological and pathological functions, including anxiety, sleepregulation, aggression, feeding and depression. Multiple serotoninreceptor subtypes have been identified and cloned. One of these, the5-HT₆ receptor, was cloned by several groups in 1993 (Ruat, M. et al.(1993) Biochem. Biophys. Res. Commun. 193: 268-276; Sebben, M. et al.(1994) NeuroReport 5: 2553-2557). This receptor is positively coupled toadenylyl cyclase and displays affinity for antidepressants such asclozapine. Recently, the effect of 5-HT₆ antagonist and 5-HT₆ antisenseoligonucleotides to reduce food intake in rats has been reported(Bentley, J. C. et al. (1999) Br J Pharmac. Suppl. 126, P66; Bentley, J.C. et al. (1997) J. Psychopharmacol. Suppl. A64, 255).

Compounds with enhanced affinity and selectivity for the 5-HT₆ receptorhave been identified, e.g. in WO 00/34242 and by Isaac, M. et al. (2000)6-Bicyclopiperazinyl-1-arylsulfonylindoles and6-Bicyclopiperidinyl-1-arylsulfonylindoles derivatives as novel, potentand selective 5-HT ₆ receptor antagonists. Bioorganic & MedicinalChemistry Letters 10: 1719-1721 (2000).

INFORMATION DISCLOSURE

J. Med. Chem. 1970, 13(4), 592-598 describesN-(4-{[2-(diethylamino)ethyl]amino}-1-naphthyl)amides;N-{5,6,7,8-Tetrahydro-4-[(3-piperidinopropyl)amino]-1-naphthyl}amidesand related amides and urea derivatives as schistosomicides.

WO 99/42465 discloses sulphonamides derivatives that bind to the 5-HT₆receptor and that can be used for the treatment of CNS disorders such asanxiety, depression, epilexy, obsessive compulsive disorders, cognitivedisorders, ADHD, anorexia and bulimia schizophrenia, drug abuse.

WO 01/32646 A1 discloses compounds that binds to the 5-HT₆ receptor andthat are used for the treatment of CNS disorders and which inter aliamay be used for the treatment of eating disorders.

WO 99/37623 A2 discloses compounds that binds to the 5-HT₆ receptor andthat are used for the treatment of CNS disorders and which inter aliamay be used for the treatment of eating disorders.

WO 99/42465 A3 discloses compounds that binds to the 5-HT₆ receptor andthat are used for the treatment of CNS disorders and which inter aliamay be used for the treatment of eating disorders.

EP 0 815 861 A1 discloses compounds that binds to the 5-HT₆ receptor andthat are used for the treatment of CNS disorders.

WO 99/02502 A2 discloses compounds that binds to the 5-HT₆ receptor andthat are used for the treatment of CNS disorders and which inter aliamay be used for the treatment of eating disorders.

WO 98/27081 A1 discloses compounds that binds to the 5-HT₆ receptor andthat are used for the treatment of CNS disorders and which inter aliamay be used for the treatment of eating disorders.

DISCLOSURE OF THE INVENTION

It has surprisingly been found that the compounds of formula (I) showaffinity for the 5-HT₆ receptor as antagonists at low nanomolar range.Compounds according to the invention and their pharmaceuticallyacceptable salts have 5-HT₆ receptor antagonist activity and arebelieved to be of potential use in the treatment or prophylaxis ofobesity and type II diabetes, as well as in the treatment or prophylaxisof disorders of the central nervous system such as anxiety, depression,panic attacks, memory disorders, sleep disorders, migraine, anorexia,bulimia, binge disorders, obsessive compulsive disorders, psychoses,Alzheimer's disease, Parkinson's disease, Huntington's chorea and/orschizophrenia, Attention Deficit Hyperactive Disorders (ADHD), drugabuse.

Definitions

Unless otherwise stated or indicated, the term “C₁₋₆ alkyl” denotes astraight or branched alkyl group having from 1 to 6 carbon atoms.Examples of said lower alkyl include methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- andbranched-chain pentyl and hexyl.

Unless otherwise stated or indicated, the term “C₁₋₆ alkoxy” denotes astraight or branched alkoxy group having from 1 to 6 carbon atoms.Examples of said lower alkoxy include methoxy, ethoxy, n-propoxy,iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight-and branched-chain pentoxy and hexoxy.

Unless otherwise stated or indicated, the term “halogen” shall meanfluorine, chlorine, bromine or iodine.

The term “C₃₋₇ cycloalkyl” denotes a cyclic alkyl group having a ringsize from C₃ to C₇. Examples of said cycloalkyl include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl and cycloheptyl.

The term “heterocyclic” refers to a hydrocarbon ring system containing 4to 8 ring members that have at least one heteroatom (e.g., S, N, or O)as part of the ring. It includes is saturated, unsaturated, aromatic,and nonaromatic heterocycles. Suitable heterocyclic groups includethienyl, furyl, pyridyl, pyrrolidinyl, imidazolyl, pyrazolyl, piperidyl,azepinyl, morpholinyl, pyranyl, dioxanyl, pyridazinyl, pyrimidinyl, andpiperazinyl groups

The term “heteroaryl” refers to a hydrocarbon ring system having atleast one aromatic ring which contains at least one heteroatom such asO, N, or S. Examples of heteroaryl groups include furyl, pyrrolyl,thienyl, oxazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl,quinazolinyl, and indolyl groups.

Compounds of Formula I

In a first aspect, the present invention provides a compound having thegeneral formula I:

or a pharmaceutically acceptable salt thereof, wherein:W is N or —(CH)—, provided that not more than three groups W are N;P is

with the proviso that P and R³ can only be in meta or para position toeach other;R¹ is(a) C₁₋₆ alkyl,(b) C₁₋₆ alkoxyalkyl,(c) straight or branched C₁₋₆ hydroxyalkyl,(d) straight or branched C₁₋₆ alkylhalides; or(e) a group Ar;Ar is(a) phenyl,(b) 1-naphthyl,(c) 2-naphthyl,(d) benzyl,(e) cinnamoyl,(f) a 5 to 7-membered, optionally aromatic, partially saturated orcompletely saturated, heterocyclic ring containing 1 to 4 heteroatoms,selected from oxygen, nitrogen and sulfur, or(g) a bicyclic ring system comprising at least one heterocyclic ringaccording to (f).

wherein the group Ar is substituted in one or more positions with

-   -   (a) H, X or Y, or    -   (b) a 5 to 7-membered, optionally aromatic, partially saturated        or completely saturated, mono- or bi-cyclic heterocyclic ring        each containing 1 to 4 heteroatoms selected from oxygen,        nitrogen or sulfur;        R² is        (a) H,        (b) C₁₋₆ alkyl,        (c) C₁₋₆ alkoxyalkyl,        (d) straight or branched C₁₋₆ hydroxyalkyl, or        (e) straight or branched C₁₋₆ alkylhalides;        R³ is a group        X and Y are independently        (a) H,        (b) halogen,        (c) C₁₋₆ alkyl,        (d) CF₃,        (e) hydroxy,        (f) C₁₋₆ alkoxy,        (g) C₁₋₄ alkenyl;        (h) phenyl;        (i) phenoxy,        (j) benzyloxy,        (k) benzoyl,        (l) —OCF₃,        (m) —CN,        (n) straight or branched C₁₋₆ hydroxyalkyl,        (o) straight or branched C₁₋₆ alkylhalides,        (p) —NH₂,        (q) —NHR⁴,        (r) —NR⁴R⁵,        (s) —NO₂,        (t) —CON R⁴R⁵,        (u) —NHSO₂ R⁴,        (v) —NR⁶COR⁵,        (x) —SO₂NR⁴R⁵,        (z) —C(═O)R⁴,        (aa) —CO₂ R⁴, or        (ab) —S(O)_(n) R⁴; wherein n is 0, 1, 2 or 3,        (ac) —S—(C₁₋₆)alkyl        (ad) —SCF₃        R⁴ and R⁵ are independently        (a) H,        (b) C₁₋₆ alkyl,        (c) C₃₋₇ cycloalkyl, or        (d) Ar, as defined above for R¹; alternatively, R⁴ and R⁵ are        linked to form a group (CH₂)₂O, (CH₂)₄O or (CH₂)₃₋₅; and        R⁶ is        (a) H, or        (b) C₁₋₆ alkyl.

In one aspect, this invention features a compound of the formula (I):

or a pharmaceutically acceptable salt thereof, wherein:ring B is

in which D is a five-membered heterocyclic or heteroaryl ring, said ringcomprising one or two atoms selected from the group consisting ofnitrogen, sulfur and oxygen, with the proviso that when D contains anoxygen atom, D is heteroaryl;W is N or —(CH)—, provided that not more than three groups W are N inboth rings A and B together;P is

P and R³ are bound to the same ring and are disposed in the meta- orpara-positions relative to each other;R¹ is(a) C₁₋₆ alkyl,(b) C₁₋₆ alkoxyalkyl,(c) straight or branched C₁₋₆ hydroxyalkyl,(d) straight or branched C₁₋₆ alkylhalides; or(e) a group Ar;Ar is(a) phenyl,(b) 1-naphthyl,(c) 2-naphthyl,(d) benzyl,(e) cinnamoyl,(f) a 5 to 7-membered, optionally aromatic, partially saturated orcompletely saturated, heterocyclic ring containing 1 to 4 heteroatoms,selected from oxygen, nitrogen and sulfur, or(g) a bicyclic ring system comprising at least one heterocyclic ringaccording to (f).

wherein the group Ar is substituted in one or more positions with

-   -   (a) H, X or Y, or    -   (b) a 5 to 7-membered, optionally aromatic, partially saturated        or completely saturated, heterocyclic ring each containing 1 to        4 heteroatoms selected from oxygen, nitrogen or sulfur;        R² is        (a) H,        (b) C₁₋₆ alkyl,        (c) C₁₋₆ alkoxy,        (d) straight or branched C₁₋₆ hydroxyalkyl, or        (e) straight or branched C₁₋₆ alkylhalides;        or R¹ and R² are linked to form a group (CH₂)₄O, which        represents (CH₂)—(CH₂)—O—(CH₂)—(CH₂);        One of R³ is a group        X and Y are independently        (a) H,        (b) halogen,        (c) C₁₋₆ alkyl,        (d) —CF₃,        (e) hydroxy,        (f) C₁₋₆ alkoxy,        (g) C₁₋₄ alkenyl;        (h) phenyl;        (i) phenoxy,        (j) benzyloxy,        (k) benzoyl,        (l) —OCF₃,        (m) —CN,        (n) straight or branched C₁₋₆ hydroxyalkyl,        (o) straight or branched C₁₋₆ alkylhalides,        (p) —NH₂,        (q) —NHR⁴,        (r) —NR⁴R⁵,        (s) —NO₂,        (t) —CONR⁴R⁵,        (u) —NHSO₂R⁴,        (v) —NR⁴COR⁵,        (x) —SO₂NR⁴R⁵,        (z) —C(═O)R⁴,        (aa) —CO₂R⁴, or        (ab) —S(O)_(n)R⁴; wherein n is 0, 1, 2 or 3;        (ac) —S—(C₁₋₆)alkyl        (ad) —SCF₃        R⁴ and R⁵ are independently        (a) H,        (b) C₁₋₆ alkyl,        (c) C₃₋₇ cycloalkyl, or        (d) Ar, as defined above for R¹;        alternatively, R⁴ and R⁵ are linked to form a group (CH₂)₂O,        (CH₂)₄O or (CH₂)₃₋₅; in which (CH₂)₂O represents (CH₂)—O—(CH₂)        and (CH₂)₄O represents (CH₂)—(CH₂)—O—(CH₂)—(CH₂); and        R⁶ is        (a) H, or        (b) straight of branched C₁₋₆ alkyl.

In preferred forms, the invention provides naphthalene compounds of theformula (II), isoquinoline compounds of the formula (III), quinolinecompounds of the formula (IV), 1,7-naphthyridine compounds of theformula (V), and benzofuran, benzothiophene, or indole compounds of theformula (VI):

wherein R³, P, X and Y are as defined for formula (I); and wherein D informula (VI) is a five-membered heterocyclic or heteroaryl ring, saidring comprising one or two atoms selected from the group consisting ofnitrogen, sulfur and oxygen, with the proviso that when D contains anoxygen atom, D is heteroaryl. The group Y can be attached to anyunsubstituted carbon atom in D. When the heteroaryl ring comprises oneor two nitrogen atoms, a group R⁶ could be attached at the secondarynitrogen.Preferred compounds of the general formulas (I), (II), (III), and (IV),(V), (VI) are those wherein:R¹ is(a) C₁₋₆ alkyl, or(e) a group Ar;Ar is(a) phenyl,(b) 1-naphthyl,(c) 2-naphthyl, or(f) a 5 to 7-membered, partially or completely saturated, mono- orbi-cyclic heterocyclic ring each containing 1 to 4 heteroatoms selectedfrom oxygen, nitrogen or sulfur;wherein the group Ar is substituted in one or more positions with X orY; wherein X or Y is(a) H,(b) halogen,(c) C₁₋₆alkyl,(d) —CF₃,(f) C₁₋₆ alkoxy,(g) C₁₋₄ alkenyl;(l) —OCF₃, or(m) straight or branched C₁₋₆ hydroxyalkyl(n) phenyloxy(o) benzyloxy(ab) —S(O)_(n)R⁴; wherein n is 0, 1, 2 or 3,(ac) —S—(C₁₋₆)alkyl(ad) —SCF₃(v) —NR⁴COR⁵,(x) —SO₂NR⁴R⁵,(z) —C(═O)R⁴.R² is(a) H, or(b) C₁₋₃ alkyl, in particular methyl;or R¹ and R² are linked to form a group (CH₂)₄O;

wherein R⁶ is

-   -   (a) H, or    -   (b) C₁₋₆ alkyl, in particular methyl;        X and Y are H; and/or        D is furanyl.

Preferred compounds of the formula II are para-substituted naphthalenecompounds wherein P is

wherein R¹ and R² are as defined for formula (I); and X and Y are H,halogens, methyl, methoxy, (cf. Table I). Particularly preferred of suchcompounds are those wherein R¹ is phenyl, methylphenyl, methoxyphenyl,dimethoxyphenyl, 1-naphthyl, 2-naphthyl, fluoromethylphenyl,chlorophenyl, dichlorophenyl, fluorochlorophenyl, dichlorothienyl,chlorothienyl, trifluoromethylphenyl, or methoxymethylphenyl; R² is H ormethyl; and R³ is piperazinyl or homopiperazinyl,3,5-dimethylpiperazine, 4-piperidine, 4-(4,3)-dihydropyridine,4-(1,2,3,6)-tetrahydropyridine; R⁶ is H, methyl, ethyl, isopropyl.Further preferred compounds of the formula II are compounds with a groupP and a group R³ in para-position.

Further preferred compounds of the formula II are compounds with a groupP and a group R³ in para-position, wherein P is

wherein R¹ and R² are as defined for formula (I) (cf. Table III); and Xor Y are H, methyl, ethyl, isopropyl, methoxy, thiomethyl, 1-naphthyl,phenyloxy, trifluoromethoxy, trifluorothienyl (cf. Table II).Particularly preferred of such compounds are those wherein R¹ is phenyl,1-naphthyl, phenyloxyphenyl, dimethoxyphenyl, dimethylphenyl,methylchlorophenyl, isopropylphenyl, fluorophenyl,1(2H)-3,4-dihydroquinolin, R² is H or methyl, R³ is piperazinyl, and R⁶is H.

Preferred compounds of the formula III are isoquinoline compoundswherein P is

and occupies position 3 of the ring, wherein R¹ and R² are as definedfor formula (I); and X or Y are H, methyl, bromo, methoxy, acethylamino(cf. Table IV). Particularly preferred of such compounds are thosewherein R¹ is phenyl, bromophenyl, methylchlorophenyl, methylphenyl,methoxyphenyl, trimethylphenyl, dimethoxyphenyl, bromomethoxyphenyl; R²is H or methyl; and R³ is methylpiperazinyl.

Preferred compounds of the formula IV are quinoline compounds wherein Pis

and occupies position 5 of the ring, wherein R¹ and R² are as definedfor formula (I); and X, Y is H (cf. Table V). Particularly preferred ofsuch compounds are those wherein R¹ is phenyl; R² is H or methyl; and R³is piperidinyl.

Preferred compounds of the formula V are 1,7-naphthyridine compoundswherein P is

and occupies position 8 of the ring, wherein R¹ and R² are as definedfor formula (I); and X and Y are halogen, methoxy (cf. Table V).Particularly preferred of such compounds are those wherein R¹ is phenyl,dimethoxyphenyl, 1-naphthyl; R² is H or methyl; and R³ is piperidinyl;

Preferred compounds of the formula VI are benzofuran compounds wherein Pis

and occupies position 5 of the ring, wherein R¹ and R² are as definedfor formula (I) and wherein D in formula (VI) is a five-memberedheterocyclic or heteroaryl ring, said ring comprising one or two atomsselected from the group consisting of nitrogen, sulfur and oxygen, withthe proviso that when D contains an oxygen atom, D is heteroaryl. Thegroup Y can be attached to any unsubstituted carbon atom in D. When theheteroaryl ring comprises one or two nitrogen atoms, a group R⁶ could beattached at the secondary nitrogen; and X and Y are halogen, methoxy(cf. Table V). Particularly preferred of such compounds are thosewherein R¹ is phenyl, dichlorophenyl, bromophenyl, dichloromethylphenyl,1-naphthyl, phenyl, methylphenyl, fluorophenyl, thiophenyl,chlorothiophenyl; R² is H or methyl; and R³ is piperidinyl orN-methylpiperidinyl.Table IPara-substituted naphthalene compounds of the formula II wherein P is

and X, Y are H:

Compound name R¹ R³ R² 1N-(4-Methylphenyl)-4-(1-piperazinyl)-1-naphthalenesulfonamide,hydrochloride

H 2 N-(2,4-Dimethoxyphenyl)-4-(1-piperazinyl)-1-naphthalenesulfonamide,hydrochloride

H 3 N-(3,4-di-Fluorophenyl)-4-(4-methyl-1,4-diazepan-1-yl)-1-naphthalenesulfonamide, hydrochloride

H 4 N-(3-Fluorophenyl)-4-(4-methyl-1,4-diazepan-1-yl)-1-naphthalenesulfonamide, hydrochloride

H 5 4-(4-Ethyl-1-piperazinyl)-N-phenyl-1-naphthalenesulfonamide,hydrochloride

H 6 4-Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl-N-(4-methylphenyl)-1-naphthalenesulfonamide, hydrochloride

H 7 N-(3,4-Dimethoxyphenyl)-4-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl-1-naphthalenesulfonamide, hydrochloride

H 84-(4-Ethyl-1-piperazinyl)-N-(4-methylphenyl)-1-naphthalenesulfonamide,hydrochloride

H 9 N-(3,4-Dimethoxyphenyl)-4-(3-methyl-1-piperazinyl)-1-naphthalenesulfonamide, hydrochloride

H 10N-(4-Methylphenyl)-4-(4-methyl-1-piperazinyl)-1-naphthalenesulfonamide,hydrochloride

H 11 N-[4-(2,5-Diazabicyclo[2.2.1]hept-2-yl)-1-naphthyl]-4-methylbenzenesulfonamide, hydrochloride

H 12N-(4-Methylphenyl)-4-(3-methyl-1-piperazinyl)-1-naphthalenesulfonamide,hydrochloride

H 13 N-(2-Naphthyl)-4-(1-piperazinyl)-1-naphthalenesulfonamide,hydrochloride

H 14N-Methyl-N-(4-methylphenyl)-4-(1-piperazinyl)-1-naphthalenesulfonamide,hydrochloride

—CH₃ 154-(1,4-Diazepan-1-yl)-N-(4-methylphenyl)-1-naphthalenesulfonamide,hydrochloride

H 16 4-(1,4-Diazepan-1-yl)-N-(2-methoxy-4-methylphenyl)-1-naphthalenesulfonamide, hydrochloride

H 17 N-(2-Methoxy-4-methylphenyl)-4-(3,5-trimethyl-1-piperazinyl)-1-naphthalenesulfonamide, hydrochloride

H 18 4-(4-Isopropyl-1-piperazinyl)-N-(4-methylphenyl)-1-naphthalenesulfonamide, hydrochloride

H 19 4-Bromo-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

H 20 2,5-di-Chloro-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide,hydrochloride

H 212-Chloro-4-fluoro-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide,hydrochloride

H 22 2,3-di-Chloro-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide,hydrochloride

H 23 2,4-di-Chloro-5-methyl-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide, hydrochloride

H 243-tri-Fluoromethyl-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide,hydrochloride

H 252-tri-Fluoromethyl-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide,hydrochloride

H 26 4-Bromo-N-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride.

CH₃ 27 Naphthalene-1-sulfonic acid(4-piperazin-1-yl-naphthalen-1-yl)-amide, hydrochloride

H 28 2,5-Dichloro-thiophene-3-sulfonic acid(4-piperazin-1-yl-naphthalen-1-yl)- amide, hydrochloride

H 29 4-Methoxy-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

H 30 4-Chloro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

H 31 2-Chloro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

H 32N-(4-Piperazin-1-yl-naphthalen-1-yl)-4-trifluoromethyl-benzenesulfonamide,hydrochloride

H 33 4-Fluoro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

H 34 5-Fluoro-2-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride

H 35 4-Phenoxy-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

H 362-Bromo-4-iodo-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

H 37 Thiophene-2-sulfonic acid (4-piperazin-1-yl-naphthalen-1-yl)-amide,hydrochloride

H 38 5-Chloro-thiophene-2-sulfonic acid(4-piperazin-1-yl-naphthalen-1-yl)-amide, hydrochloride

H 39 3-Methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

H 40 4-Butyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamidehydrochloride

H 412,4,6-Trimethyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamidehydrochloride

H 422,4,5-Trichloro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

H 43 4-Iodo-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

H 44 2-Methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

H 453,4-Dichloro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

H 46 5-Bromo-2-methoxy-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride

H 47 2-Bromo-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

H 48 3-Chloro-2-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride

H 492,6-Dichloro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

H 50 3-Methoxy-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

H 51 3-Chloro-4-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride

H 524-Bromo-2-fluoro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

H 53 2,4-Dichloro-6-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride

H

54 4-Bromo-2-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride

H 55 4,5-Dichloro-thiophene-2-sulfonic acid(4-piperazin-1-yl-naphthalen-1-yl)- amide, hydrochloride

H 56 N-Methyl-N-(4-bromo-2-methylphenyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide, hydrochloride

CH₃ 57 N-Methyl-N-(5-fluoro-2-methylphenyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide, hydrochloride

CH₃ 58N-Methyl-N-(2-methylphenyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide,hydrochloride

CH₃ 59 N-Methyl-N-(3-chloro-2-methylphenyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide, hydrochloride

CH₃ 602,5-di-Chlorothiophen-3-yl-N-Methyl-N-(2,5-dichlorothiophen-3-yl)-4-(1-pyperazinyl)-1-napthalenesulphonamide, hydrochloride

2

CH₃ 61N-Methyl-N-(1-naphthyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide,hydrochloride

CH₃ 62N-Methyl-N-(1-naphthyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide,hydrochloride

CH₃ 63N-Methyl-N-(4-chlorophenyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide,hydrochloride

CH₃ 64 N-Methyl-N-(4-methoxyphenyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide, hydrochloride

CH₃ 65 5-Fluoro-2-methyl-N-{4-[(2R,5S)-2,5-dimethyl-1-]piperazin-1-yl-1-naphthyl}benzenesulfonamide, hydrochloride

H 66 5-Fluoro-2-methyl-N-[4-(1,2,3,6-tetrahydropyridin-4-yl)-1-naphthyl]benzenesulfonamide, hydrochloride

H3-Substituted naphthalene compounds of the formula II wherein P is

and X, Y are H: TABLE II

Compound name R¹ R³ R² 67N-[4-(Methyl-1-piperazinyl)-2-naphthyl]benzenesulfonamide, hydrochloride

H5-Substituted naphthalene compounds of the formula II wherein P is

and X, Y and R⁴ are H: TABLE III

Compound name R¹ R³ R² 68 4-Piperazin-1-yl-naphthalene-1-sulfonic acidphenylamide, hydrochloride

H 69 4-Piperazin-1-yl-naphthalene-1-sulfonic acid(2-methoxy-phenyl)-amide, hydrochloride

H 70 4-(cis-3,5-Dimethyl-piperazin-1-yl)-naphthalene-1-sulfonic acid(2-methoxy- phenyl)-amide, hydrochloride

H 71 4-(cis-3,5-Dimethyl-piperazin-1-yl)-naphthalene-1-sulfonic acid(3-chloro-phenyl)- amide, hydrochloride

H 72 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid(3-chloro-phenyl)-amide, hydrochloride

H 73 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid phenylamidehydrochloride

H 74 4-Piperazin-1-yl-naphthalene-1-sulfonic acid(3-chloro-phenyl)-amide, hydrochloride

H 75 4-Piperazin-1-yl-naphthalene-1-sulfonic acid(2-methylsulfanyl-phenyl)-amide, hydrochloride

H 76 4-Piperazin-1-yl-naphthalene-1-sulfonic acidmethyl-naphthalen-1-yl-amide, hydrochloride

H 77 4-Piperazin-1-yl-naphthalene-1-sulfonic acid(2,3-dihydro-benzo[1,4]dioxin-6-yl)- methyl-amide, hydrochloride

CH₃ 78 4-Piperazin-1-yl-naphthalene-1-sulfonic acid(2,3-dihydro-benzo[1,4]dioxin-6-yl)- amide, hydrochloride

H 79 4-Piperazin-1-yl-naphthalene-1-sulfonic acidmethyl-(2-methylsulfanyl-phenyl)- amide, hydrochloride

CH₃ 80 4-Piperazin-1-yl-naphthalene-1-sulfonic acid,methyl-(3-trifluoromethyl-phenyl)- amide, hydrochloride

CH₃ 81 4-Piperazin-1-yl-naphthalene-1-sulfonic acid(3-chloro-4-methyl-phenyl)-methyl- amide, hydrochloride

CH₃ 82 4-Piperazin-1-yl-naphthalene-1-sulfonic acid(3-ethyl-phenyl)-methyl-amide, hydrochloride

CH₃ 83 4-(3,5-Dimethyl-piperazin-1-yl)-naphthalene-1-sulfonic acid(2-isopropyl-phenyl)- amide, hydrochloride

H 84 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid(2-isopropyl-phenyl)-amide, hydrochloride

H 85 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid(3-ethyl-phenyl)-amide, hydrochloride

H 86 N-(2-Fluorophenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide,hydrochloride

H 87 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid(3-trifluoromethyl-phenyl)-amide, hydrochloride

H 88 N-(2,4-di-Fluorophenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide,hydrochloride

H 89 4-Piperazin-1-yl-naphthalene-1-sulfonic acid(2-trifluoromethoxy-phenyl)-amide, hydrochloride

H 90 4-Piperazin-1-yl-naphthalene-1-sulfonic acid(3-trifluoromethoxy-phenyl)-amide, hydrochloride

H 91 4-Piperazin-1-yl-naphthalene-1-sulfonic acid(3-trifluoromethoxy-phenyl)-amide, hydrochloride

H 92 4-Piperazin-1-yl-naphthalene-1-sulfonic acid(2-chloro-5-methyl-phenyl)-amide, hydrochloride

H 93 4-Piperazin-1-yl-naphthalene-1-sulfonic acid(4-isopropyl-phenyl)-amide, hydrochloride

H 94 N-(3,5-di-Fluorophenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide,hydrochloride

H 95 1-[4-(3,4-Dihydroquinolin-1(2H)-ylsulfonyl)-1-naphthyl]piperazine,hydrochloride

H 96 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid(3-nitro-phenyl)-amide, hydrochloride

H 97 4-Piperazin-1-yl-naphthalene-1-sulfonic acid(3-nitro-phenyl)-amide, hydrochloride

H 98 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid(3-nitro-phenyl)-methyl-amide, hydrochloride

CH₃ 99 N-(4-methylphenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide,hydrochloride

H 100N-(3-chloro-4-methylphenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide,hydrochloride

H 101 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid(2,3-dimethyl-phenyl)-methyl- amide, hydrochloride

CH₃ 102 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid(4-isopropyl-phenyl)-amide, hydrochloride

H 103 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid(4-isopropyl-phenyl)-methyl- amide, hydrochloride

CH₃ 104 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid(2,4-dimethyl-phenyl)-amide, hydrochloride

H 105 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid(2-chloro-5-methyl-phenyl)-amide, hydrochloride

H 106 4-Piperazin-1-yl-naphthalene-1-sulfonic acid(2,5-dimethoxy-phenyl)-amide, hydrochloride

H 107 4-Piperazin-1-yl-naphthalene-1-sulfonic acid(3-acetyl-phenyl)-amide, hydrochloride

H 108 4-Piperazin-1-yl-naphthalene-1-sulfonic acid(2,4-dimethyl-phenyl)-amide, hydrochloride

H 109 4-Piperazin-1-yl-naphthalene-1-sulfonic acid(3-trifluoromethyl-phenyl)-amide, hydrochloride

H 110 4-Piperazin-1-yl-naphthalene-1-sulfonic acid biphenyl-2-ylamide,hydrochloride

H 111 4-Piperazin-1-yl-naphthalene-1-sulfonic acid(3-benzyloxy-phenyl)-amide, hydrochloride

H 112 N-(4-fluorophenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide,hydrochloride

H 113 N-(3-Ethylphenyl)-4-piperazin.1.ylnaphthalene-1-sulphonamine,hydrochloride

H 1144-Piperazinyl-N-[3-(trifluoromethyl)phenyl]naphthalene-1-sulfonamide,hydrochloride

H 115 4-Piperazinyl-N-[3-benzoylphenyl]naphthalene-1-sulfonamide,hydrochloride

H 1164-Piperazinyl-N-[3-(4-bromo-1-methyl-1H-pyrazol-3-yl)phenyl]naphthalene-1-sulfonamide, hydrochloride

H 117 4-Piperazinyl-N-[3-biphenylphenyl]naphthalene-1-sulfonamide,hydrochloride

H

Meta-substituted isoquinoline compounds of the formula III wherein P is

and X, Y are H: TABLE IV

Compound name R¹ R³ R² 118 N-[1-(4-methyl-1-piperazinyl)-3-isoquinolinyl]benzenesulfonamide, hydrochloride

H 119 2,4-di-Fluoro-N-[1-(4-methyl-1- piperazinyl)-3-isoquinolinyl]benzenesulfonamide, hydrochloride

H 120 4-Bromo-N-[1-(4-methyl- piperazin-1-yl)-isoquinolin-3-yl)-benzenesulfonamide, hydrochloride

H 121 5-Chloro-3-methyl- benzo[b]thiophene-2-sulfonic acid[1-(4-methyl-piperazin-1-yl)- isoquinolin-3-yl]-amide, hydrochloride

H 122 3-Chloro-2-methyl-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]- benzenesulfonamide, hydrochloride

H 123 3,4-Dichloro-N-[1 -(4-methyl- piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonamide, hydrochloride

H 124 4-Methyl-N-[1-(4-methyl- piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonamide, hydrochloride

H 125 3-Methoxy-N-[1-(4-methyl- piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonamide, hydrochloride

H 126 5-Chloro-thiophene-2-sulfonic acid [1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-amide, hydrochloride

H 127 N-{2-Chloro-4-[1-(4-methyl- piperazin-1-yl)-isoquinolin-3-ylsulfamoyl]-phenyl}-acetamide hydrochloride

H 128 2,5-Dichloro-thiophene-3-sulfonic acid[1-(4-methyl-piperazin-1-yl)- isoquinolin-3-yl]-amide, hydrochloride

H 129 N-[1-(4-Methyl-piperazin-1-yl)-isoquinolin-3-yl]-3-trifluoromethyl- benzenesulfonamide, hydrochloride

H 130 N-[1-(4-Methyl-piperazin-1-yl)- isoquinolin-3-yl]-4-phenoxy-benzenesulfonamide, hydrochloride

H 131 5-Bromo-2-methoxy-N-[1-(4- methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonamide, hydrochloride

H 132 2-Methanesulphonayl-N-[1-(4- methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonamide, hydrochloride

H 133 3,5-Dimethyl-isoxazole-4-sulfonic acid[1-(4-methyl-piperazin-1-yl)- isoquinolin-3-yl]-amide, hydrochloride

H 134 2,4,6-Trimethyl-N-[1-(4-methyl- piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonamide, hydrochloride

H 135 3,4-Dimethoxy-N-[1-(4-methyl- piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonamide, hydrochloride

H5-Substituted quinoline compounds of the formula IV wherein P is

and X, Y are H: TABLE V

Compound name R¹ R³ R² 136 N-(8-{[2-(di- Methylamino)ethyl]amino}-5-quinolinyl)benzenesulfonamide, hydrochloride

H1.7-Naphthyridine compounds of the formula V wherein P is

R² and X, Y are H: TABLE VI

Compound name R1 R3 137 4-Methyl-N-(8-piperazin-1-yl-1,7-naphthyridin-6- yl)benzenesulfonamide, trifluoroacetic acid

138 4-Bromo-N-(8-piperazin-1- yl-1,7-naphthyridin-6-yl)benzenesulfonamide, trifluoroacetic acid

139 N-(8-Piperazin-1-yl-1,7- naphthyridin-6- yl)naphthalene-1-sulfonamide, trifluoroacetic acid

140 N-(8-Piperazin-1-yl-1,7- naphthyridin-6-yl)butane-1- sulfonamide,trifluoroacetic acid

141 3-Trifluoromethyl-N-(8- piperazin-1-yl-1,7- naphthyridin-6-yl)benzenesulfonamide, trifluoroacetic acid

142 3,4-Dimethoxy-N-(8- piperazin-1-yl-1,7- naphthyridin-6-yl)benzenesulfonamide, trifluoroacetic acid

143 2,4-Dichloro-N-(8- piperazin-1-yl-1,7- naphthyridin-6-yl)benzenesulfonamide, trifluoroacetic acid

144 N-(8-Piperazin-1-yl-1,7- naphthyridin-6- yl)thiophene-2-sulfonamide, trifluoroacetic acid

145 1-Phenyl-N-(8-piperazin-1- yl-1,7-naphthyridin-6-yl)methanesulfonamide, trifluoroacetic acid

5-Substituted benzofuran compounds of the formula VI wherein P is

R² and X, Y are H: TABLE VII

Compound name R1 R3 1463-Cyanophenyl-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,hydrochloride

147 4-Phenoxy-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,hydrochloride

148 1-Naphthyl-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,hydrochloride

149 N-(7-Piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,hydrochloride

150 5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonic acid(7-piperazin-1-yl-benzofuran-5-yl)-amide, hydrochloride

151 N-[7-(4-Methylpiperazin-1-yl)-1-benzofuran-5-yl]-benzenesulfonamide,hydrochloride

152 4-Methyl-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,hydrochloride

1533,4-Dimethoxy-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,hydrochloride

154 4-Bromo-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,hydrochloride

1552,3-Dichloro-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,hydrochloride

1562,4-Dichloro-5-methyl-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,hydrochloride

157 4-Methoxy-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,hydrochloride

158 4-Chloro-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,hydrochloride

159N-(7-Piperazin-1-yl-benzofuran-5-yl)-4-trifluoromethyl-benzenesulfonamide,hydrochloride

1605-Fluoro-2-methyl-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,hydrochloride

161 5-Chloro-thiophene-2-sulfonic acid(7-piperazin-1-yl-benzofuran-5-yl)-amide, hydrochloride

Methods for Preparation

The compounds according to the invention (Tables I, II, IV, V, VI) canbe prepared starting from halo-nitro substituted bicyclic aromatic ringsby base (potassium carbonate) catalyzed aromatic nucleophilicsubstitution of a halogen in the desired position of the centralbicyclic ring with the diamine of choice (R³). Reduction of a nitrogroup properly positioned on the central bicyclic ring by Raney-Nicatalyzed reaction leads to the aniline that is substituted further bysulfonylation with the alkyl- or aryl-sulfonylchloride of choice(R¹—SO₂—Cl). Scheme 1 and Scheme 3

The compounds according to the invention (Tables III) can be preparedstarting from fluoro substituted bicyclic aromatic rings in which thesulfonylchloride functionality is introduced by acid catalyzedsulfonylation. The sulfonyl group is reacted further with anilines ofchoice (R¹—NH₂). The diamine group (R³) is introduced by base catalyzedaromatic nucleophilic substitution. Scheme 2

The compounds according to the invention (Tables VII) can be preparedstarting from iodo substituted bicyclic aromatic rings. The diaminegroup (R³) is introduced by Palladium catalysed nucleophilicsubstitution. Reduction of a nitro group properly positioned on thecentral bicyclic ring by Raney-Ni catalyzed reaction leads to theaniline that is substituted further by sulfonylation with the alkyl- oraryl-sulfonylchloride of choice (R¹—SO₂—Cl). Scheme 4

The chemicals used in the above-described synthetic route may include,for example, solvents, reagents, catalysts, protecting group anddeprotecting group reagents. The methods described above may alsoadditionally include steps, either before or after the steps describedspecifically herein, to add or remove suitable protecting groups inorder to ultimately allow synthesis of the compounds of formula (I). Inaddition, various synthetic steps may be performed in an alternatesequence or order to give the desired compounds. Synthetic chemistrytransformations and protecting group methodologies (protection anddeprotection) useful in synthesizing applicable compounds are known inthe art and include, for example, those described in R. Larock,Comprehensive Organic Transformations, VCH Publishers (1989); T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2^(nd)Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser andFieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); andL. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, JohnWiley and Sons (1995) and subsequent editions thereof.

Depending on the process conditions, the end products of the formula (I)are obtained either in neutral or salt form. Both the free base and thesalts of these end products are within the scope of the invention.

Acid addition salts of the new compounds may in a manner known per se betransformed into the free base using basic agents such as alkali or byion exchange. The free base obtained may also form salts with organic orinorganic acids.

In the preparation of acid addition salts, preferably such acids areused which form suitably therapeutically acceptable salts. Examples ofsuch acids are hydrohalogen acids, sulfuric acid, phosphoric acid,nitric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxyl orsulfonic acids, such as formic acid, acetic acid, propionic acid,succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid,citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvicacid, p-hydroxybensoic acid, embonic acid, methanesulfonic acid,ethanesulfonic acid, hydroxyethanesulfonic acid, halogenbensenesulfonicacid, toluenesulfonic acid, mandelic acid or naphthalenesulfonic acid.

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and optical isomers andracemates thereof where such isomers exist. All diastereomeric formspossible (pure enantiomers, tautomers, racemic mixtures and unequalmixtures of two enantiomers) are within the scope of the invention. Suchcompounds can also occur as cis- or trans-, E- or Z-double bond isomerforms. All isomeric forms are contemplated.

Pharmaceutical formulations are usually prepared by mixing the activesubstance, or a pharmaceutically acceptable salt thereof, withconventional pharmaceutical excipients. The formulations can be furtherprepared by known methods such as granulation, compression,microencapsulation, spray coating, etc.

This invention relates to a method of treatment or prophylaxis ofobesity, type II diabetes, and/or disorders of the central nervoussystem. The method includes administering to a subject (e.g., a mammal,a human, a horse, a dog, or a cat) in need thereof an effective amountof one or more compounds of the formula (I) described above.

This invention also features a method for reducing body-weight (e.g.,treating body-weight disorders) or reducing food intake. The methodincludes administering to a subject in need thereof an effective amountof a compound of the formula (I). As used herein, the term “body weightdisorders” refers to the disorders caused by an imbalance between energyintake and energy expenditure, resulting in abnormal body (e.g.,excessive) weights. Such body weight disorders include obesity.

Also within the scope of this invention is a method for modulating(e.g., inhibiting) 5-HT₆ receptor activity. The method includesadministering to a subject in need thereof an effective amount of acompound of the formula (I).

The methods delineated herein can also include the step of identifyingthat the subject is in need of treatment of obesity, type II diabetes,or disorders of the central nervous system, or in need of reducingbody-weight or reducing food intake.

“An effective amount” refers to an amount of a compound which confers atherapeutic effect on the treated subject. The therapeutic effect may beobjective (i.e., measurable by some test or marker) or subjective (i.e.,subject gives an indication of or feels an effect). For clinical use,the compounds of the invention are formulated into pharmaceuticalformulations for oral, rectal, parenteral or other mode ofadministration. Usually the amount of active compounds is between0.1-95% by weight of the preparation, preferably between 0.2-20% byweight in preparations for parenteral use and preferably between 1 and50% by weight in preparations for oral administration.

The typical daily dose of the active substance varies within a widerange and will depend on various factors such as, for example, theindividual requirement of each patient and the route of administration.In general, oral and parenteral dosages will be in the range of 5 to1000 mg per day of active substance, preferably 50 to 150 mg per day.

The specific examples below are to be construed as merely illustrative,and not limitative of the remainder of the disclosure in any waywhatsoever. Without further elaboration, it is believed that one skilledin the art can, based on the description herein, utilize the presentinvention to its fullest extent. All publications cited herein arehereby incorporated by reference in their entirety.

EXAMPLES Synthesis of Examples and Intermediates in Table I

In scheme 1, the following symbols are used: (i) K₂CO₃, DMF, diamine ofchoice; (ii) H₂, Raney-Ni or Pd/C, THF:Ethanol; (iii) (BOC)₂O, NaOH;(iv) R¹—SO₂—Cl, Py, CH₂Cl₂; (v) HCl in diethyl ether; (vi) alkylhalides.TfO=trifluoromethanesulfonate.General Method AReduction of Nitronapthalenes Derivatives to Naphthylamine Derivatives

To a solution of nitronapthalenes derivatives (1 eq) in EtOH:THF (4:1)was added is Raney-Ni (˜1.0 mL suspension in EtOH) followed by hydrazinemonohydrate (6 eq). The mixtures are stirred vigorously for 3 hours andthen filtered through celite pretreated with water. The filtrate wasconcentrated, followed by the addition of toluene. Purifications areperformed by flash column chromatography (SiO₂, CHCl₃/MeOH/NH₃ 9:1:0.4%and 2 parts of light petroleum) to obtain the free base of napthylaminederivatives.

General Method B

Reaction of 4-nitro-chloronaphthalenes with diamines

Diamines (1.2 eq) are added to a suspension of chloronaphthalenesderivatives (1 eq) and K₂CO₃ (3.5) in DMF. The suspensions are stirredat 65° C. for 16 hours followed by filtration. Elimination of volatilesto give a crude residue. The residues are purified by flashchromatography (SiO₂, CHCl₃→CHCl₃/10% MeOH/0.4% aq. NH₃) to give thecorresponding products as free bases.

(a) Intermediates for Preparation of Compounds in Tables I, II, IV and VAccording to Scheme 1

Intermediate 1

1-Methyl-4-(4-nitro-1-naphthyl)-1,4-diazepane—To a suspension of1-chloro-4-nitronaphthalene (1.0 g, 4.82 mmol) and K₂CO₃ (2.0 g, 14.46mmol) in DMF (10 mL) was added 1-methyl-1,4-diazepane (0.66 g, 5.78mmol). The suspension was stirred at 65° C. for 16 hours followed byfiltration. Elimination of volatiles to give a crude residue. Theresidue was purified by flash chromatography (SiO₂, CHCl₃→CHCl₃/10%MeOH/0.4% aq. NH₃) to give 0.79 g (57%) of the free base: ¹H NMR (CDCl₃)δ 8.85-8.75 (m, 1H), 8.35-8.25 (m, 1H), 8.20-8.12 (m, 1H), 7.70-7.60 (m,1H), 7.55-7.45 (m, 1H), 6.97-6.90 (m, 1H), 3.70-3.55 (m, 4H), 2.83-2.71(m, 4H), 2.44 (s, 3H), 2.09-1.97 (m, 2H); ¹³C NMR (CDCl₃) δ 157.47,139.13, 129.26, 127.82, 127.66, 126.53, 125.69, 125.40, 123.94, 111.22,58.37, 57.37, 55.44, 54.71, 46.97, 27.88; MS (posES-FIA) m/z=found285.1463, calc 285.1477.

Intermediate 2

4-(4-Methyl-1,4-diazepan-1-yl)-1-naphthylamine—To a solution of1-methyl-4-(4-nitro-1-naphthyl)-1,4-diazepane (0.793 g, 2.78 mmol) in 40mL of EtOH:THF (4:1) was added Raney-Ni (˜1.0 mL suspension in EtOH)followed by hydrazine monohydrate (0.696 g, 13.9 mmol). The mixture wasstirred vigorously for 3 hours and then filtered through celitepretreated with water. The filtrate was concentrated, followed by theaddition of toluene. Purification by flash column chromatography (SiO₂,CHCl₃/MeOH/NH₃ 9:1:0.4% and 2 parts of light petroleum) gave 0.441 g(62%) of the free base: ¹H NMR (CDCl₃) δ 8.37-8.29 (m, 1H), 7.85-7.76(m, 1H), 7.55-7.40 (m, 2H), 7.07-7.01 (m, 1H), 6.75-6.68 (m, 1H), 3.96(br s, 2H), 3.36-3.20 (m, 4H), 2.95-2.76 (m, 4H), 2.48 (s, 3H),2.10-1.95 (m, 2H); MS (posESI) m/z=256 (M+H).

Intermediate 3

1-Ethyl-4-(4-nitro-1-naphthyl)piperazine—To a mixture of1-chloro-4-nitronaphthalene (0.794 g, 3.82 mmol), and K₂CO₃ (0.791 g,5.73 mmol) in DMF (3 mL) was added N-ethyl piperazine (0.486 mL, 3.82mmol). The mixture was heated in a microwave oven at 100 W for 1 minute.The reaction mixture was allowed to cool down and the procedure wasrepeated 5 times. The mixture was filtered and concentrated. The crudeproduct was purified by column chromatography (SiO₂,CHCl₃→CHCl₃/MeOH/NH₃ 9:1:0.4%) to give 0.950 g (87%) of a reddish brownsolid: ¹H NMR (CDCl₃) δ 8.75-8.70 (m, 1H), 8.30 (d, J=8.4 Hz, 1H),8.24-8.20 (m, 1H), 7.72-7.66 (m, 1H), 7.60-7.54 (m, 1H), 7.02 (d, J=8.4Hz, 1H), 3.32-3.24 (m, 4H), 2.85-2.70 (m, 4H), 2.54 (q, J=7.3 Hz, 2H),1.17 (tr, J=7.3 Hz, 3); MS (posEI) m/z 385 (M⁺).

Intermediate 4

(cis)-3,5-Dimethyl-1-(4-nitro-1-naphthyl)piperazine—This compound wasprepared from 1-chloro-4-nitronaphthalene (0.481 g, 2.32 mmol) andcis-2,6-dimethylpiperazine (0.481 g, 2.32 mmol) by the method describedabove, yield 0.554 g (84%) of the pure product as a reddish brown solid;¹H NMR (CDCl₃) δ 8.76-8.71 (m, 1H), 8.30 (d, J=8.4 Hz, 1H), 8.23-8.14(m, 1H), 7.72-7.66 (m, 1H), 7.61-7.55 (m, 1H), 7.0 (d, J=8.4 Hz, 1H),3.45-3.37 (m, 2H), 3.35-3.25 (m, 2H), 2.55-2.47 (m, 2H), 1.17-1.4 (m,6H); MS (posEI) m/z 385 (M⁺).

Intermediate 5

3-Methyl-1-(4-nitro-1-naphthyl)piperazine—This compound was preparedfrom 1-chloro-4-nitronaphthalene (0.395 g, 1.90 mmol) and2-methylpiperazine (0.395 g, 1.90 mmol) by the method described above:yield 0.470 g (84%) of the pure product as a solid; ¹H NMR (CDCl₃) δ8.75-8.70 (m, 1H), 8.29 (d, J=8.55 Hz, 1H), 8.24-8.20 (m, 1H), 7.72-7.65(m, 1H), 7.61-7.55 (m, 1H), 7.00 (d, J=8.55 Hz, 1H), 3.46-3.37 (m, 2H),3.31-3.15 (m, 3H), 2.95-2.89 (m, 1H), 2.61-2.53 (m, 1H), 1.15 (d, J=6.4Hz, 3H)); MS (EI) m/z 271 (M⁺).

Intermediate 6

2-(4-Nitro-1-naphthyl)octahydropyrrolo[1,2-a]pyrazine—This compound wasprepared from 1-chloro-4-nitronaphthalene (0.306 g, 1.47 mmol) andoctahydropyrrolo[1,2-a]pyrazine (0.185 g, 1.47 mmol) by the methoddescribed above, yield 0.332 g (76%) of the pure product as a yellowoil; ¹H NMR (CDCl₃) δ 8.75-8.71 (m, 1H), 8.29 (d, J=8.5 Hz, 1H),8.23-8.20 (m, 1H), 7.72-7.67 (m, 1H), 7.60-7.55 (m, 1H), 7.05 (d, J=8.5Hz, 1H), 3.64-3.59 (m, 1H), 3.54-3.48 (m, 1H), 3.27-3.10 (m, 3H),2.90-2.80 (m, 1H), 2.70-2.65 (m, 1H), 2.60-2.30 (m, 2H), 2.00-1.80 (m,3H), 1.65-1.50 (m, 1H); MS (posESI) m/z 298 (M+H).

Intermediate 7

1-(4-Nitro-1-naphthyl)-1,4-diazepane—To a solution of1-chloro-4-nitronaphthalene (0.971 g, 4.68 mmol) and K₂CO₃ (0.973 g,7.10 mmol) in CH₃CN (5.0 mL) was added homopiperazine (0.711 g, 7.10mmol). The reaction mixture was heated in a closed sealed vessel at 120°C. in a microwave oven for 10 min. The suspension was filtered andconcentrated. Purification by column chromatography (SiO₂,CHCl₃→CHCl₃/MeOH 9:1) gave 0.952 g of the pure product; ¹H NMR (CDCl₃) δ8.80-8.74 (m, 1H), 8.29 (d, J=8.5 Hz, 1H), 8.25-8.19 (m, 1H), 7.71-7.63(m, 1H), 7.57-7.49 (m, 1H), 7.03 (d, J=8.5 Hz, 1H), 3.57-3.48 (m, 4H),3.18-3.10 (m, 4H), 2.10-1.95 (m, 2H); MS (posEI) m/z 272 (M⁺).

Intermediate 8

tert-Butyl4-(4-nitro-1-naphthyl)-1-piperazinecarboxylate—1-Chloro-4-nitronaphthalene(2.7 g, 13 mmol), tert-butyl-1-piperazinecarboxylate (2.4 g, 13 mmol)and potassium carbonate (2 g) were heated together in DMSO (100 mL) at90° C. overnight. The solution was allowed to cool to room temperatureand poured into water (500 mL). The product was collected by filtrationand recrystallised from methanol/water to yield 2.8 g (60%) of the titlecompound; mp 158.2° C.; ¹H NMR (CDCl₃) δ 1.52 (s, 9H), 3.2 (br, 4H),3.75 (br, 4H), 7.04 (d, J=8.53 Hz, 1H), 7.62 (t, J=7.02 Hz, 1H), 7.73(t, J=7.02 Hz, 1H), 8.25 (d, J=8.53 Hz, 1H), 8.3 (d, J=8.54 Hz, 1H),8.73 (d, J=8.53 Hz, 1H).

Intermediate 9

1-tert-Butyl4-(4-{bis[(4-methylphenyl)sulfonyl]amino}-1-naphthyl)-1-piperazinecarboxylate—tert-Butyl4-(4-nitro-1-naphthyl)-1-piperazinecarboxylate (1 g, 2.8 mmol) inethanol (200 mL) was hydrogenated at atmospheric pressure over Pd/C(10%, 0.2 g) for 3 hours after which time the uptake of hydrogen ceased.The solution was filtered and evaporated. The residue was dissolved intoluene (100 mL) and evaporated to give an off white solid. The solidwas dissolved in acetonitrile (50 mL) containing 4-dimethylaminopyridine(0.73 g). Toluene sulfonyl chloride (1.14 g, 6 mmol) was added and themixture stirred at 35° C. overnight. Brine was added and the productextracted into ethyl acetate (2×100 mL). The organic extracts were driedover MgSO₄ and evaporated to give a pale brown solid which wasre-crystallized from ethanol. Yield 1.04 g (58%) of a white solid. Mp176-178; ¹H NMR (400 MHz, CDCl₃) δ 1.40 (s, 9H), 2.36 (s, 6H), 3.0 (br,4H), 3.6 (br, 4H), 6.81 (AB, J=8.03 Hz, 1H), 6.89 (AB, J=8.03 Hz, 1H),7.17 (m, 1H), 7.19 (d, J=7.53 Hz, 4H), 7.32 (m, 1H), 7.45 (d, J=8.53 Hz,1H), 7.70 (d, J=8.54 Hz, 4H), 8.03 (d, J=8.03 Hz, 1H).

Intermediate 10

1-tert-Butyl4-(4-{[(4-methylphenyl)sulfonyl]amino}-1-naphthyl)-1-piperazinecarboxylate—1-tert-Butyl4-(4-{bis[(4-methylphenyl)sulfonyl]amino}-1-naphthyl)-1-piperazinecarboxylate(1 g, 1.6 mmol) was dissolved in ethanol (50 mL). Potassium hydroxide(85%, 0.54 g) was added and the solution refluxed for 12 hours. Thesolution was poured into water (100 mL) and acidified with acetic acid(0.6 mL). The product precipitated and was collected by filtration,washed with water and dried. Yield 0.81 g; ¹H NMR (400 MHz, CDCl₃) δ1.36 (s, 9H), 2.22 (s, 3H), 2.8 (br, 4H), 3.5 (br, 4H), 6.47 (s, 1H),6.79 (d, J=8.03 Hz, 1H), 7.03 (d, J=8.03 Hz, 2H), 7.07 (d, J=8.03 Hz,1H), 7.3 (m, 2H), 7.47 (d, J=8.53 Hz, 2H), 7.69 (1, J=9.04 Hz, 1H), 8.03(d, J=7.02 Hz, 1H).

Intermediate 11

1-tert-Butyl4-(4-{methyl[(4-methylphenyl)sulfonyl]amino)-1-naphthyl)-1-piperazinecarboxylate—1-tert-Butyl4-(4-{[(4-methylphenyl)sulfonyl]amino}-1-naphthyl)-1-piperazinecarboxylate(0.1 g, 0.2 mmol) was dissolved in DMSO (5 mL) and potassium carbonate(0.2 g) and methyl iodide (0.1 g) were added. The mixture was stirredand heated at 85° C. for 15 hours. The solution was poured into water(50 mL) and the product collected by filtration, washed with water anddried. Yield 0.078 g (78%) of a white solid. ¹H NMR (400 MHz, CDCl₃) δ1.60 (s, 9H), 2.56 (s, 3H), 3.1 (br, 4H), 3.36 (s, 3H), 3.7 (br, 4H),6.90 (AB, J=8.03 Hz, 1H), 6.97 (AB, J=8.03 Hz, 1H), 7.41 (d, J=8.03 Hz,2H), 7.6 (m, 2H), 7.75 (d, J=8.29 Hz, 2H), 8.3 (m, 2H).

Intermediate 12

5-Nitro-8-quinolinyl trifluoromethanesulfonate—To a solution of5-nitro-8-quinolinol (1.89 g, 9.40 mmol) and Et₃N (6.60 mL, 4.70 mmol)in CH₂Cl₂ (125 mL) was added N-phenyl-trifluoromethanesulfonimide (5.06g, 14.1 mmol). The mixture was stirred at room temperature for 16 hoursand then more of added N-phenyl-trifluoromethanesulfonimide (1.0 equiv.)was added and the mixture was stirred from another 16 hours. Thereaction mixture was washed with 10% aqueous NaHCO₃, dried with K₂CO₃,filtered and concentrated. The crude residue was triturated in MeOH togive 1.2 g (40%) of the pure product: ¹H NMR (CDCl₃) δ 9.20-9.18 (m,1H), 9.11-9.07 (m, 1H), 8.48-8.45 (m, 1H), 7.83-7.79 (m, 1H), 7.76-7.72(m, 1H); MS (posEI-DIP) m/z 321 (M+H).

Intermediate 13

8-(4-Methyl-1-piperazinyl)-5-nitroquinoline—To a suspension of5-nitro-8-quinolinyl trifluoromethanesulfonate (0.50 g, 1.56 mmol) andK₂CO₃ (0.43 g, 3.12 mmol) in CH₃CN (6.0 mL) was added 1-methylpiperazine(0.19 mL, 1.71 mmol). The suspension was stirred at room temperature for16 hours. The mixture was filtered and concentrated. Purification viaflash column chromatography (SiO₂, CHCl₃/MeOH/NH₃ 9:1:0.4%) gave 0.509 gof the pure product: reversed phase HPLC>95% purity; MS (posESI) m/z 273(M+H).

Intermediate 14

tert-Buyl(2R,6S)-2,6-dimethyl-4-(4-nitro-1-naphthyl)-1-piperazinecarboxylate—To asolution of cis-3,5-dimethyl-1-(4-nitro-1-naphthyl)piperazine (0.565 g,1.98 mmol) and NaOH (0.198 g, 4.95 mmol) in THF:water (20 mL, 1:1) wasadded di-tert-butyl dicarbonate (1.30 g, 5.94 mmol) in THF (4 mL). Thereaction mixture was stirred at room temperature for 4 hours followed bythe addition of 3.0 equiv. of di-tert-butyl dicarbonate and 2.5 equiv.of NaOH. The mixture was stirred at room temperature for another 3 days.The mixture was concentrated and extracted with CHCl₃ (3×20 mL). Thecombined organic phases were dried with K₂CO₃, filtered andconcentrated. The crude residue was purified by column chromatography onsilica using CHCl₃ as eluent gave 0.200 g (26%) of the pure product as asolid brown solid: MS (posESI) m/z 386 (M+H).

Intermediate 15

tert-Butyl-2-methyl-4-(4-nitro-1-naphthyl)-1-piperazinecarboxylate wasprepared from 3-methyl-1-(4-nitro-1-naphthyl)piperazine (0.436 g, 1.61mmol) by the method described above: yield 0.552 g (92%) of the pureproduct as a yellow oil; ¹H NMR (CDCl₃) δ 8.73-8.70 (m, 1H), 8.34-8.30(m, 1H), 8.28 (d, J=8.5 Hz, 1H), 7.74-7.69 (m, 1H), 7.63-7.58 (m, 1H),7.02 (d, J=8.5 Hz, 1H), 4.50-4.442 (m, 1H), 4.10-4.03 (m, 1H), 3.52-3.39(m, 2H), 3.32-3.27 (m, 1H), 3.08-3.03 (m, 1H), 2.89-2.82 (m, 1H), 1.53(s, 3H), 1.51 (s, 9H); MS (posESI) m/z 372 (M+H).

Examples of Compounds According to the Invention Example 14-Methyl-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide,hydrochloride

1-tert-Butyl4-(4-{[(4-methylphenyl)sulfonyl]amino}-1-naphthyl)-1-piperazinecarboxylate(intermediate 10) (0.4 g, 0.8 mmol) was dissolved in THF (20 mL) andtreated with a 1N solution of HCl in diethyl ether (30 mL) for twelvehours. The product was collected as a pale pink solid. Yield 0.2 g(60%). mp 181° C. (dec); ¹H NMR (DMSO-d₆) δ 2.80 (s, 3H), 3.1 (br, 4H),3.3 (br, 4H), 7.00 (q, J=8.06 Hz, 2H), 7.27 (ab, J=8.30 Hz, 2H), 7.4-7.5(m, 2H), 7.53 (ab, J=8.30 Hz, 2H), 7.99 (d, J=8.06 Hz, 1H), 8.07 (d,J=7.57 Hz, 1H), 9.2 (br, 2H); MS (ESI+) for C21 H23 N3 O2 S Found m/z381.1499 M⁺ Calc. 381.1611.

Example 23,4-Dimethoxy-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide,hydrochloride

tert-Butyl 4-(4-nitro-1-naphthyl)-1-piperazinecarboxylate (1 g, 2.8mmol) in ethanol (200 mL) was hydrogenated at atmospheric pressure overPd/C (10%, 0.2 g) for 3 hours after which time the uptake of hydrogenceased. The solution was filtered and evaporated. The residue wasdissolved in toluene (100 mL) and evaporated to give an off white solid.The solid was dissolved in acetonitrile (50 mL) containing4-dimethylaminopyridine (0.73 g). This solution was divided into threeportions. To one portion was added 3,4-dimethoxybenzene sulfonylchloride (0.24 g). The mixture was stirred for 4 hours at 40° C. undernitrogen. Ethyl acetate (50 mL) was added and the solution washed withbrine (2×100 mL). The organic phase was separated, dried over MgSO₄ andevaporation. Purification by flash chromatography (SiO₂, Petrol:Ethylacetate 1:1) afforded the butoxycarbonyl protected product which wasdissolved in methanol (2 mL) and treated with a 1N solution of HCl inethyl acetate (25 mL) for three hours. The product was precipitated withether (200 mL) and collected as a pale pink solid, 45 mg (12%). ¹H NMR(DMSO-d₆) δ 3.17 (br, 4H), 3.35 (br, 4H), 3.63 (s, 3H), 3.78 (s, 3H),7.03 (d, J=8.55 Hz, 1H), 7.07 (ab, J=13.92, 8.06 Hz, 2H), 7.24 (dd,J=8.30, 2.19 Hz, 1H), 7.46 (m, 1H), 7.51 (m, 1H), 8.05 (d, J=7.57 Hz,1H), 8.12 (d, J=7.56 Hz, 1H), 9.2 (br, 2H), 9.93 (s, 1H); MS (ESI+) forC22 H25 N3 O4 S m/z 427 (M+H)⁺.

Example 33,4-di-Fluoro-N-[4-(4-methyl-1,4-diazepan-1-yl)-1-naphthyl]benzenesulfonamide,hydrochloride

To a solution of (intermediate 2)4-(4-methyl-1,4-diazepan-1-yl)-1-naphthylamine (0.173 g, 0.676 mmol) andpyridine (0.450 mL, 4.73 mmol) in CH₂Cl₂ (3 mL) was added a solution of2,4-Di-fluorobenzenesulfonyl chloride (0.158 g, 0.743 mmol) in CH₂Cl₂ (2mL). The mixture was stirred at room temperature for 16 hours and thenconcentrated. The crude mixture was purified by column chromatographychromatography (SiO₂, CHCl₃/MeOH/NH₃ 9:1:0.4%). The free base wasconverted to its HCl-salt and recrystallized from MeOH and ether to give0.227 g (79%) of the salt: ¹H NMR (DMSO-d6) δ 11.23 (br s, 1H), 10.49(s, 1H), 8.21-8.17 (m, 1H), 7.72-7.65 (m, 1H), 7.55-7.46 (m, 3H),7.19-7.10 (m, 3H), 3.65-3.35 (m, 6H), 3.30-3.15 (m, 2H), 2.85-2.82 (m,3H), 2.33-2.10 (m, 2H); MS (posES-FIA) m/z 432 (M+H).

Example 43-Fluoro-N-[4-(4-methyl-1,4-diazepan-1-yl)-1-naphthyl]benzenesulfonamide,hydrochloride

To a solution of (intermediate 3 after reduction according to Method A)4-(4-methyl-1,4-diazepan-1-yl)-1-naphthylamine (0.173 g, 0.676 mmol) andpyridine (450 μL, 4.73 mmol) in CH₂Cl₂ (3.0 mL) was added3-fluorobenzenesulfonyl chloride (0.145 g, 0.743 mmol) in CH₂Cl₂ (1.0mL). The solution was stirred at room temperature for 16 hours and thevolatiles were evaporated. The crude product was purified by columnchromatography (SiO₂, CHCl₃/MeOH/NH₃ 9:1:0.4%) to give 240 mg of theproduct as solid that was triturated with MeOH/ether to give 0.180 g(64%) of the free base which was converted to its HCl-salt: ¹H NMR(DMSO-d6) δ 11.07 (br s, 1H), 10.28 (br s, 1H), 8.20-8.16 (m, 1H),7.98-7.94 (m, 1H), 7.60-7.40 (m, 6H), 7.16-7.12 (m, 1H), 7.06-7.02 (m,1H), 3.65-3.30 (m, partly obscured by solvent signal, HDO, 6H),3.26-3.18 (m, 2H), 2.84 (s, 3H), 2.30-2.05 (m, 2H); MS (posES-FIA)m/z=414 (M+H).

Example 5 N-[4-(4-Ethyl-1-piperazinyl)-1-naphthyl]benzenesulfonamide,hydrochloride

The title compound was prepared from (intermediate 3 after reductionaccording to Method A) 4-(4-ethyl-1-piperazinyl)-1-naphthylamine (0.241g, 0.945 mmol) and benzenesulfonyl chloride (0.121 mL, 0.945 mmol) bythe method described above to yield HCl-salt 0.210 g (51%); ¹H NMR(CD₃OD) δ 8.19-8.15 (m, 1H), 7.94-7.90 (m, 1H), 7.70-7.66 (m, 2H),7.56-7.46 (m, 2H), 7.44-7.36 (m, 3H), 7.19 (d, J=8.0 Hz, 1H), 7.11 (d,J=8.0 Hz, 1H), 3.75-3.40 (m, 6H), 3.34 (q, J=7.6 Hz, 2H), 3.25-3.10 (m,2H), 1.43 (tr, J=7.6 Hz, 3H); MS (posEI) m/z 387 (M⁺).

Example 6N-(4-Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl-1-naphthyl)-4-methylbenzenesulfonamide,hydrochloride

To a solution of (intermediate 6)2-(4-nitro-1-naphthyl)octahydropyrrolo[1,2-a]pyrazine (0.160 g, 0.54mmol) in 10 mL THF:EtOH (20 mL, 1:4) was added Raney-Ni (1.0 mLsuspension in EtOH) followed by hydrazine hydrate (0.135 g, 2.70 mmol).The mixture was stirred vigorously at room temperature for 16 hours andthen filtered through celite pretreated with water. The filtrate wasconcentrated and the residue was dissolved in CH₂Cl₂ (3 mL) and pyridine(0.35 mL, 3.78 mmol) and p-toluensulfonyl chloride (0.13 g, 0.54 mmol)were added to the solution. The reaction mixture was stirred at roomtemperature for 16 hours and then concentrated. The crude product waspurified by column chromatography chromatography (SiO₂, CHCl₃/MeOH/NH₃9:1:0.4%) to give 0.217 g (95%) of the free base which was converted toits HCl-salt: ¹H NMR (CD₃OD) δ 8.21-8.14 (m, 1H), 7.97-7.93 (m, 1H),7.58-7.47 (m, 3H), 7.43-7.37 (m, 1H), 7.25-7.10 (m, 4H), 4.12-4.02 (m,1H), 3.80-3.0 (m, partly obscured by solvent signal, 8H), 2.45-2.10 (m,3H), 2.35 (s, 3H), 1.87-1.75 (m, 1H); MS (posEI) m/z 421 (M⁺).

Example 7N-(4-Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl-1-naphthyl)-3,4-dimethoxybenzenesulfonamide,hydrochloride

The title compound was prepared from (intermediate 6)2-(4-nitro-1-naphthyl)octahydropyrrolo[1,2-a]pyrazine (0.133 g, 0.447mmol) by the method described above: yield 0.160 g (76%) of the pureproduct as the free base which was converted to its HCl-salt; ¹H NMR(CD₃OD) δ 8.20-8.16 (m, 1H), 7.96-7.92 (m, 1H), 7.54-7.48 (m, 1H),7.43-7.38 (m, 1H), 7.30-7.26 (m, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.16 (d,J=8.0 Hz, 1H), 7.09-7.07 (m, 1H), 6.95-6.92 (m, 1H), 3.83 (s, 3H),3.82-3.0 (m, partly obscured by solvent signal, 10H), 3.62 (s, 3H),2.50-2.10 (m, 2H); MS (posEI) m/z 467 (M⁺).

Example 8N-[4-(4-Ethyl-1-piperazinyl)-1-naphthyl]-4-methylbenzenesulfonamide,hydrochloride

To a solution of (intermediate 3 after reduction according to Method A)4-(4-ethyl-1-piperazinyl)-1-naphthylamine 0.241 g, 0.945 mmol) andpyridine (0.534 mL, 0.945 mmol) in CH₂Cl₂ (3.0 mL) was addedp-toluenesulfonyl chloride (0.180 g, 0.945 mmol) in CH₂Cl₂ (2.0 mL). Themixture was stirred at room temperature for 16 hours followed by theaddition of CH₂Cl₂ (15 mL). The reaction mixture was washed withsaturated aqueous NaHCO₃, dried with Na₂SO₄, filtered and concentrated.The crude residue was purified by column chromatography (SiO₂.CHCl₃→CHCl₃/MeOH/NH₃ 9:1:0.4%) to give a solid which was converted toits HCl-salt: yield HCl-salt 0.372 g (88%); ¹H NMR (CD₃OD) δ 8.20-8.15(m, 1H), 7.97-7.93 (m, 1H), 7.58-7.54 (m, 2H), 7.53-7.47 (m, 1H),7.43-7.37 (m, 1H), 7.25-7.20 (m, 2H), 7.18 (d, J=8.0 Hz, 1H), 7.10 (d,J=8.0 Hz, 1H), 3.80-3.10 (m, partly obscured by solvent signal, 10H),2.35 (s, 3H), 1.43 (tr, J=7.3 Hz, 3H); MS (posEI) m/z 409 (M⁺).

Example 93,4-Dimethoxy-N-[4-(3-methyl-1-piperazinyl)-1-naphthyl]benzenesulfonamide,hydrochloride

The title compound was prepared from (intermediate 8 after reductionaccording to Method A) tert-butyl4-(4-amino-1-naphthyl)-2-methyl-1-piperazinecarboxylate (0.189 g, 0.55mmol) and 3,4-dimethoxybenzenesulfonyl chloride (0.130 g, 0.55 mmol) bythe method described above: yield HCl-salt 0.068 g (26%); 1H NMR (CD₃OD)

Example 104-Methyl-N-[4-(4-methyl-1-piperizinyl)-1-naphthyl]-1-benzenesulfonamide,hydrochloride

To a solution of 4-(4-methyl-1-piperazinyl)-1-naphthylamine (preparedaccording to methods A and B) (0.099 g, 0.409 mmol) and pyridine (231μL, 2.86 mmol) in CH₂Cl₂ (3.0 mL) was added 4-methylbenzenesulfonylchloride (0.078 g, 0.409 mmol) in CH₂Cl₂ (1.0 mL). The solution wasstirred at room temperature for 16 hours and then washed with saturatedaqueous NaHCO₃, dried with Na₂SO₄, filtered and concentrated. The crudeproduct was purified via column chromatography (SiO₂,CHCl₃→CHCl₃/MeOH/NH₃ 9:1:0.4%) to give the pure base which was convertedto its HCl-salt: yield 110 mg (62%); ¹H NMR (DMSO-d6) δ 10.86 (br s,1H), 10.02 (s, 1H), 8.11-8.03 (m, 2H), 7.60-7.56 (m, 2H), 7.55-7.44 (m,2H), 7.33-7.30 (m, 2H), 7.09-7.06 (m, 1H), 7.04-7.01 (m, 1H), 3.55-3.32(m, 6H), 3.19-3.10 (m, 2H), 2.86 (s, 3H), 2.34 (s, 3H); MS (posES-FIA)m/z=395.1665 (M+H)(calc 395.1667).

Example 114-Methyl-N-[4-(5-methyl-2,5-diazabicyclo[2,2,1]hept-2-yl]-naphtyl]benzenesulfonamide,hydrochloride

To a solution of4-(5-methyl-2,5-diazabicyclo[2,2,1]hept-2-yl)-1-naphtylamine (0.210 g,0.829 mmol) (prepared according to methods A and B), pyridine (468 μL,5.80 mmol) in CH₂Cl₂ (3.0 mL) was added 4-methylbenzenesulfonyl chloride(0.158 g, 0.829 mmol) in CH₂Cl₂ (1.0 mL). The solution was stirred atroom temperature for 16 hours and then concentrated. The crude productwas purified via column chromatography (SiO₂, CHCl₃→CHCl₃/MeOH/NH₃9:1:0.4%) to give the pure base which was converted to its HCl-salt:yield 160 mg (43%); ¹H NMR (DMSO-d6) δ 10.78 (br s, 1H), 9.90-9.88 (m,1H), 8.02-7.98 (m, 2H), 7.58-7.55 (m, 2H), 7.49-7.41 (m, 2H), 7.33-7.30(m, 2H), 7.06-7.03 (m, 1H), 6.93-6.90 (m, 1H), 4.38-4.30 (m, 3H),3.65-3.60 (m, 3H), 2.90-2.87 (m, 1H), 2.86-2.83 (m, 3H), 2.36 (br s,2H), 2.35 (s, 3H); MS (posES-FIA) m/z=407.1655 (M+H)(calc 407.1667).

Example 124-Methyl-N-[4-(3-methyl-1-piperazinyl)-1-naphthyl]benzenesulfonamide,hydrochloride

To a solution of (intermediate 8 after resuction according to Method A)tert-butyl 4-(4-amino-1-naphthyl)-2-methyl-1-piperazinecarboxylate (0189g, 0.55 mmol) and pyridine (0.311 mL, 3.85 mmol) in CH₂Cl₂ (3 mL) wasadded tolouenesulfonyl chloride (0.105 g, 0.55 mmol). The mixture wasstirred at room temperature for 16 hours and then concentrated. Thecrude residue was purified by column chromatography (SiO₂, EtOAc:pentane3:7). The pure intermediate was dissolved in small amount of MeOH andde-protected using ether saturated with HCl-gas. The precipitate wascollected by filtration and triturated with MeOH and ether: yieldHCl-salt 0.047 g (19%); ¹H NMR (CDCl₃) δ 8.28-8.20 (m, 1H), 7.85-7.79(m, 1H), 7.65-7.55 (m, 1H), 7.50-7.10 (m, partly obscured by solventsignal, 5H), 6.95-6.85 (m, 1H), 6.51 (br s, 1H), 4.50-4.25 (m, 1H),4.05-3.85 (m, 1H), 3.52-3.33 (m, 1H), 3.28-3.05 (m, 2H), 2.97-2.85 (m,1H), 2.82-2.67 (m, 1H), 2.85 (s, 3H), 1.52-1.47 (m, partly obscured byH₂O signal, 3H); MS (pos-ES) m/z=395 (M+H).

Example 13 2-N-[4-(1-piperazinyl)-1-naphthyl]naphthalenesulfonamide,hydrochloride

To another portion of the solution of the reduced nitro compound wasadded 2-naphthalenesulfonyl chloride (0.23 g). The mixture was stirredfor 4 hours at 40° C. under nitrogen and worked up as above. The productobtained was identified as 1-tert-butyl4-(4-{bis[(2-naphthalene)sulfonyl]amino}-1-naphthyl)-1-piperazinecarboxylate.This bis sulfonamide was refluxed for 3 hours in ethanol (10 mL)containing NaOH (0.1 g). This solution was added to a solution of HCl inethyl acetate (1N, 100 mL) and stirred overnight. The solution wasevaporated to give the crude product which was purified by preparativehplc (CH₃CN:H₂O 10% to 50% gradient). Yield 47 mg. ¹H NMR (400 MHz,DMSO-d₆) δ 3.05 (br, 4H), 3.3 (br, 4H), 7.0 (s, 2H), 7.2-7.5 (m, 2H),7.55 (t, J=7.9 Hz, 1H), 7.62 (t, J=6.9 Hz, 1H), 7.76 (m, 1H), 7.9-8.1(m, 5H), 8.21 (s, 1H), 8.7 (br, 2H)

Example 14

N,4-Dimethyl-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide,hydrochloride 1-tert-Butyl4-(4-{methyl[(4-methylphenyl)sulfonyl]amino}-1-naphthyl)-1-piperazinecarboxylate(intermediate 14 after reduction according to Method A) (75 mg, 0.15mmol) was dissolved in methanol (5 mL) and treated with 1N HCl in ether(20 mL). After stirring overnight, the product precipitated and wascollected by filtration, washed with ether and dried. Yield 60 mg (92%)of an off white solid.

Example 15N-[4-(1,4-Diazepan-1-yl)-1-napthyl]-4-methylbenzenesulfonamide,hydrochloride

To a solution of (intermediate 7 after reduction according to Method A)4-(1,4-diazepan-1-yl)-1-naphtylamine (0.399 g, 1.17 mmol), pyridine (661μL, 8.19 mmol) and Et₃N (329 μL, 2.34 mmol in CH₂Cl₂ (3.0 mL) was added4-methylbenzenesulfonyl chloride (0.223 g, 1.17 mmol) in CH₂Cl₂ (1.0mL). The solution was stirred at room temperature for 16 hours and thenconcentrated. The crude product was purified via column chromatography(SiO₂, CHCl₃→CHCl₃/MeOH/NH₃ 9:1:0.4%) to give 0.360 g of theboc-protected compound. De-protection was accomplished by dissolving theintermediate in MeOH and then adding HCl-gas dissolved in ether. Theprecipitate was collected by filtration to give 0.143 g (28%) of thepure compound as the HCl-salt: ¹H NMR (DMSO-d6) δ 10.00 (s, 1H), 9.28(br s, 1H), 8.20-8.16 (m, 1H), 8.04-7.99 (m, 1H), 7.60-7.55 (m, 2H),7.54-7.49 (m, 1H), 7.47-7.42 (m, 1H), 7.33-7.29 (m, 2H), 7.12 (d, J=8.16Hz, 1H), 7.01 (d, J=8.16 Hz, 1H), 3.42-3.31 (m, 6H), 3.20.3.16 (m, 2H),2.34 (s, 3H), 2.14-2.08 (m, 2); MS (posES-FIA) m/z=395.1667 (M+H) (calc395.1667)

Example 16N-[4-(1,4-Diazepan-1-yl)-1-napthyl]-2-methoxy-4-methylbenzenesulfonamide,hydrochloride

To a solution of (intermediate 7 after reduction according to Method A)4-(1,4-diazepan-1-yl)-1-napthylamine (0.399 g, 1.17 mmol), pyridine (661μL, 8.19 mmol) and Et₃N (329 μL, 2.34 mmol in CH₂Cl₂ (3.0 mL) was added2-methoxy-4-methylbenzenesulfonyl chloride (0.258 g, 1.17 mmol) inCH₂Cl₂ (1.0 mL). The solution was stirred at room temperature for 16hours and then concentrated. The crude product was dissolved in EtOH andpowdered KOH was added to the solution. The mixture was stirred at 70°C. for 16 hours. The suspension was concentrated and water was added.The solution was neutralized with 1N HCl and extracted with CH₂Cl₂ (2×20mL). The combined organic phases were washed with brine, dried withNa₂SO₄, and concentrated. Column chromatography (SiO₂,CH₂Cl₂→CH₂Cl₂/MeOH (95:5) gave 0.432 g of a reddish brown solid.De-protection of the intermediate using MeOH ether saturated withHCl-gas gave brown solid which was collected by filtration. The productwas re-crystallized from MeOH/ether to give 109 mg (20%) of product asits HCl-salt: ¹H NMR (DMSO-d6) δ 9.74 (s, 1H), 9.36 (br s, 2H),8.20-8.14 (m, 2H), 7.55-7.45 (m, 3H), 7.44-7.42 (m, 1H), 7.16-7.09 (m,2H), 7.02-7.00 (m, 1H), 6.75-6.74 8 m, 1H), 3.85 (s, 3H), 3.42-3.27 (m,6H), 3.18-3.14 (m, 2H), 2.31-(s, 3H), 2.14-2.07 (m, 2H); MS (posES-FIA)m/z=425.1768 (M+H)(calc 425.1774)

Example 17N-(2-Methoxy-4-methylphenyl)-4-(3,5-trimethyl-1-piperazinyl)-1-naphthalenesulfonamide,hydrochloride

To a solution of (intermediate 4 after reduction according to Method A)4-(2,6-dimethyl-1-piperazinyl)-1-naphthylamine (0.203 g, 0.563 mmol) andpyridine (322 μL, 3.99 mmol) in DCM (3.0 mL) was added4-methylbenzenesulfonyl chloride (0.107 g, 0.563 mmol) in DCM (1.0 mL).The solution was stirred at room temperature for 16 hours and thenwashed with saturated aqueous NaHCO₃, dried with Na₂SO₄, filtered andconcentrated. The crude intermediate was purified via columnchromatography on silica using CHCl₃/CHCl₃+10% MeOH+0.4% NH₃ to give0.230 g of the boc-protected intermediate. Removal of the boc-group wasaccomplished by dissolving the intermediate in MeOH and then addingether saturated with HCl-gas. The crude product was dissolved in DCM andthen purified via column chromatography on silica using CHCl₃/CHCl₃+10%MeOH+0.4% NH₃ to give 156 mg (67%) of the pure base which was convertedto its HCl-salt: 1H NMR (DMSO-d6) δ 10.01 (s, 1H), 9.86-9.78 (m, 1H),9.14-9.00 (m, 1H), 8.13-8.10 (m, 1H), 8.05-8.02 (m, 1H), 7.58-7.55 (m,2), 7.53-7.49 (m, 1H), 7.48-7.43 (m, 1H), 7.33-7.29 (m, 2H), 7.06 (d,J=7.85 Hz, 1H), 7.02 (d, J=8.17 Hz, 1H), 3.65-3.55 (m, 2H), 3.35-3.27(m, 2H), 2.86-2.79 (m, 2H), 2.34 (s, 3H), 1.31 (d, J=6.60 Hz, 6H); MS(posES-FIA) m/z=409.1838 (M+H)(calc 407.1824)

Example 18N-[4-(4-Isopropyl-1-piperizinyl)-1-naphthyl]-4-methylbenzenesulfonamide,hydrochloride

To a solution of 4-(4-isopropyl-1-piperazinyl)-1-naphthylamine (0.209 g,0.776 mmol) (prepared according to Methods A and B) and pyridine (438μL, 5.43 mmol) in CH₂Cl₂ (3.0 mL) was added 4-methylbenzenesulfonylchloride (0.163 g, 0.850 mmol) in CH₂Cl₂ (1.0 mL). The solution wasstirred at room temperature for 16 hours and the solid was collected byfiltration as the HCl-salt to yield 0.236 g (66%); ¹H NMR (DMSO-d6) δ10.65 (br s, 1H), 9.95 (br s, 1H), 8.10-8.05 (m, 1H), 8.02-7.94 (m, 1H),7.56-7.49 (m, 2H), 7.48-7.37 (m, 2H), 7.28-7.22 (m, 2H), 7.02-6.94 (m,2H), 3.53-3.40 (m, 3H), 3.37-3.15 (m, 8H), 2.28 (s, 3H), 1.32-1.28 (m,6H); MS (posES-FIA) m/z=423.1972 (M+H)(calc 423.1980).

Example 194-Bromo-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 10.21 (s, 1H), 9.12 (brs, 2H), 8.12 (d, J=8.48 Hz,1H), 7.97 (d, J=8.16 Hz., 1H), 7.75-7.70 (m, 2H), 7.61-7.57 (m, 2H),7.54-7.49 (m, 1H), 7.48-7.43 (m, 1H), 7.10-7.01 (M, 2h), 3.38-3.31 (M,4H), 3.23-3.10 (M, 4H), MS (posESI) m/z=446 (M+H).

Example 202,5-Dichloro-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide,hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ 3.2 (br, 4H), 3.4 (br, 4H), 7.09 (s, 2H),7.54 (m, 2H), 7.70 (m, 3H), 8.10 (m, 2H); MS (ESI+) for C20 H19 Cl2 N3O2 S m/z 436 (M+H)⁺.

Example 212-Chloro-4-fluoro-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide,hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ 3.1 (br, 4H), 3.4 (br, 4H), 7.01 (AB, J=8.03Hz, 1H), 7.04 (AB, J=8.03 Hz, 1H), 7.27 (dt, J=3.01, 8.53 Hz, 1H), 7.5(m, 2H), 7.68 (dd, J=2.51, 9.03 Hz, 1H), 7.85 (dd, J=6.52, 9.03 Hz, 1H),8.10 (d, J=7.03 Hz, 1H), 8.20 (d, J=7.03 Hz, 1H); MS (ESI+) for C20 H19Cl F N3 O2 S m/z 420 (M+H)⁺.

Example 222,3-Dichloro-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide,hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ 3.1 (br, 4H), 3.4 (br, 4H), 7.01 (AB, J=8.03Hz, 1H), 7.03 (AB, J=8.03 Hz, 1H), 7.42 (t, J=7.78 Hz, 1H), 7.50 (m,2H), 7.81 (dd, J=1.51, 8.03 Hz, 1H), 7.85 (dd, J=1.51, 8.03 Hz, 1H),8.10 (dd, J=6.52, 2.0 Hz, 1H), 8.20 (dd, J=7.53, 2.01 Hz, 1H); MS (ESI+)for C20 H19 Cl2 N3 O2 S m/z 436 (M+H)⁺.

Example 232,4-Dichloro,5-methyl-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide,hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ 2.27 (s, 3H), 3.15 (br, 4H), 3.4 (br, 4H),7.07 (s, 2H), 7.54 (m, 2H), 7.79 (s, 1H), 7.85 (s, 1H), 8.13 (m, 1H),8.19 (m, 1H); MS (ESI+) for C21 H21 Cl2 N3 O2 S m/z 450 (M+H)⁺.

Example 243-Trifluoromethyl-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide,hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ 3.2 (br, 4H), 3.4 (br, 4H), 7.05 (AB, J=8.03Hz, 1H), 7.10 (AB, J=8.03 Hz, 1H), 7.40 (t, J=7.53 Hz, 1H), 7.50 (t,J=7.53 Hz, 1H), 7.76 (t, J=8.03 Hz, 1H), 7.81 (s, 1H), 7.88 (d, J=8.53Hz, 1H), 7.95 (d, J=8.03 Hz, 1H), 7.99 (d, J=8.03 Hz, 1H), 8.12 (d,J=8.54 Hz, 1H); MS (ESI+) for C21 H20 F3 N3 O2 S m/z 436 (M+H)⁺.

Example 252-Trifluoromethyl-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide,hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ 3.0 (br, 4H), 3.4 (br, 4H), 6.93 (s, 2H),7.36 (m, 1H), 7.41 (m, 1H), 7.64 (m, 2H), 7.85 (dd, J=2.01, 7.53 Hz,1H), 7.90 (dd, J=2.01, 7.03 Hz, 1H), 8.02 (d, J=8.54 Hz, 2H).

Example 264-Bromo-N-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 9.12 (brs, 2H), 8.22-8.07 (m, 2H), 7.89 (d, J=8.44Hz, 2H), 7.74-7.58 (m, 4H), 7.10 (d, J=7.91 Hz, 1H), 6.89 (d, 8.18 Hz,1H), 3.50 (s, 3H), 3.43-3.27 (m, obscured in part by solvent signal), MS(posESI) m/z=460 (M+H).

Example 27 Naphthalene-1-sulfonic acid(4-piperazin-1-yl-naphthalen-1-yl)-amide, hydrochloride

¹H NMR (DMSO-d6) δ; 9.00 (brs, 1H), 8.77-8.71 (m, 1H), 8.18 (d, J=8.44Hz, 1H), 8.10-8.02 (m, 2H), 8.01-7.96 (m, 1H), 7.90 (d, J=8.18 Hz, 1H),7.73-7.62 (m, 2H), 7.56-7.49 (m, 1H), 7.47-7.39 (m, 1H), 7.31-7.23 (m,1H), 7.02-6.94 (m, 2H), 3.40-3.25 (m, obscured by solvent signal),3.19-3.05 (m, 4H), MS (posESI) m/z=418 (M+H).

Example 28 2,5-Dichloro-thiophene-3-sulfonic acid(4-piperazin-1-yl-naphthalen-1-yl)-amide, hydrochloride

¹H NMR (DMSO-d6) δ; 10.52 (brs, 1H), 9.02 (brs, 2H), 8.19-8.12 (m, 1H),8.01-7.94 (m, 1H), 7.60-7.47 (m, 2H), 7.23-7.12 (m, 3H), 3.43-3.28 (m,obscured in part by solvent signal), 3.25-3.10 (m, m, 4H), MS (posESI)m/z=442 (M+H).

Example 294-Methoxy-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 9.96 (s, 1H), 9.13 (brs, 1H), 8.15-8.08 (m, 1H),8.06-7.99 (m, 1H), 7.65-7.57 (m, 2H), 7.55-7.42 (m, 2H), 7.12-6.97 (m,4H), 3.43-3.29 (m, 4H), 3.24-3.10 (m, 4H), MS (posESI) m/z=398 (M+H).

Example 304-Chloro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 10.25 (brs, 1H), 9.03 (brs, 1H), 8.16-8.09 (m, 1H),8.00-7.94 (m, 1H), 7.71-7.41 (m, 6H), 7.13-7.01 (m, 2H), 3.40-3.26 (m,obscured in part by solvent signal), 3.24-3.08 (m, 4H), MS (posESI)m/z=402 (M+H).

Example 312-Chloro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

¹H NMR (CDCl₃) δ; 8.24-8.12 (m, 2H), 7.90-7.83 (m, 1H), 7.60-7.43 (m,3H), 7.32-7.27 (m, obscured in part by solvent signal, 1H), 7.09 (s,1H), 7.04 (d, J=8.44 Hz, 1H), 6.87-6.79 (m, 1H), 3.90-3.40 (m, 4H),3.12-2.80 (m, 4H), MS (posESI) m/z=402 (M+H).

Example 32N-(4-piperazin-1-yl-naphthalen-1-yl)-4-trifluoromethyl-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 10.40 (brs, 1H), 9.03 (brs, 1H), 8.12 (d, J=7.65 Hz,1H), 7.95-7.83 (m, 5H), 7.55-7.39 (m, 2H), 7.13-7.02 (m, 2H), 3.40-3.30(m, obscured in part by solvent signal), 3.23-3.09 (m, 4H), MS (posESI)m/z=436 (M+H).

Example 334-Fluoro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 10.17 (brs, 1H), 9.18 (brs, 2H), 8.15-8.08 (m, 1H),7.99-7.92 (m, 1H), 7.77-7.66 (m, 2H), 7.55-7.30 (m, 4H), 7.11-7.01 (m,2H), 3.40-3.30 (m, obscured by solvent signal), 3.25-3.10 (m, 4H), MS(posESI) m/z=386 (M+H).

Example 345-Fluoro-2-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 10.27 (brs, 1H), 9.19 (brs, 2H), 8.16-8.10 (m, 1H),8.03-7.96 (m, 1H), 7.58-7.33 (m, 5H), 7.12-6.98 (m, 2H), 3.40-3.30 (m,obscured by solvent signal) 3.24-3.10 (m, 4H), MS (posESI) m/z=400(M+H).

Example 354-Phenoxy-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 10.08 (s, 1H), 9.11 (brs, 2H), 8.18-8.07 (m, 1H),7.98-7.89 (m, 1H), 7.67-7.60 (m, 2H), 7.57-7.40 (m, 4H), 7.28-7.20 (m,1H), 7.11 (s, 2H), 7.07-6.98 (m, 1H), 7.11 (s, 2H), 7.07-6.98 (m, 4H),3.40-3.30 (m, obscured by solvent signal), 3.24-3.10 (m, 4H), MS(posESI) m/z=460 (M+H).

Example 362-Bromo-4-iodo-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 10.45 (brs, 1H), 9.01 (brs, 2H), 8.28 (d, J=1.58 Hz,1H), 8.18-8.09 (m, 2H), 7.88-7.83 (m, 1H), 7.59-7.50 (m, 3H), 7.07 (s,2H), 3.40-3.30 (m, obscured by solvent signal), 3.23-3.10 (m, 4H), MS(posESI) m/z=572 (M+H).

Example 37 Thiophene-2-sulfonic acid(4-piperazin-1-yl-naphthalen-1-yl)-amide, hydrochloride

¹H NMR (DMSO-d6) δ; 10.30 (s, 1H), 9.12 (brs, 1H), 8.17-8.09 (m, 1H),8.00-7.92 (m, 1H), 7.89-7.85 (m, 1H), 7.56-7.38 (m, 3H), 7.18-7.06 (m,3H), 3.40-3.30 (m, obscured by solvent signal), 3.25-3.15 (m, 4H), MS(posESI) m/z=374 (M+H).

Example 38 5-Chloro-thiophene-2-sulfonic acid(4-piperazin-1-yl-naphthalen-1-yl)-amide, hydrochloride

¹H NMR (DMSO-d6) δ; 10.43 (brs, 1H), 9.11 (brs, 2H), 8.19-8.111 (m, 1H),8.02-7.95 (m, 2H), 7.29 (d, J=3.95 Hz, 1H), 7.21-7.12 (m, 3H), 3.40-3.30(m, obscured by solvent signal), 3.25-3.15 (m, 4H), MS (posESI) m/z=408(M+H).

Example 393-Methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 8.14-8.07 (m, 1H), 8.04-7.97 (m, 1H), 7.55-7.35 (m,6H), 7.07-6.97 (m, 2H), 3.30-2.98 (m, obscured in part by solventsignal, 8H), 2.29 (s, 3H), MS (posESI) m/z=442 (M+H).

Example 404-Butyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamidehydrochloride

¹H NMR (DMSO-d6) δ; 10.05 (s, 1H), 9.20 (brs, 2H), 8.11 (d, J=7.91 Hz,1H), 7.93 (d, J=8.18 Hz, 1H), 7.62-7.26 (m, 5H), 7.07 (s, 2H), 3.40-3.30(m, obscured by solvent signal), 3.25-3.15 (m, 4H), 2.66-2.55 (m,obscured in part by solvent signal, 2H), 1.58-1.15 (m, 2H), 1.32-1.15(m, 2H), 0.92-0.83 (m, 3H), MS (posESI) m/z=427 (M+H).

Example 412,4,6-Trimethyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 9.92 (brs, 1H), 9.01 (brs, 2H), 8.15-8.09 (m, 1H),8.05-7.98 (m, 1H), 7.55-7.42 (m, 2H), 7.09-6.94 (m, 4H), 3.40-3.30 (m,obscured by solvent signal), 3.25-3.15 (m, 4H) 2.85 (s, 6H), 2.22 (s,3H), MS (posESI) m/z=410 (M+H).

Example 422,4,5-Trichloro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 10.68 (brs, 1H), 9.06 (brs, 1H), 8.22-8.08 (m, 2H),8.18 (s, 1H), 7.88 (s, 1H), 7.61-7.52 (m, 2H), 7.09 (s, 2H), 3.40-3.30(m, obscured by solvent signal), 3.25-3.15 (m, 4H), MS (posESI) m/z=470(M+H).

Example 434-Iodo-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 10.22 (s, 1H), 9.06 (brs, 2H), 8.16-8.09 (m, 1H),8.02-7.87 (m, 3H), 7.58-7.39 (m, 4H), 7.18-6.98 (m, 2H), 3.40-3.30 (m,4H), 3.25-3.10 (m, 4H), MS (posESI) m/z=494 (M+H).

Example 442-Methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 10.13 (s, 1H), 9.15 (brs, 2H), 8.15-8.08 (m, 1H),8.07-7.63 (m, 1H), 7.70-7.63 (m, 1H), 7.61-7.23 (m, 2H), 3.41-3.27 (m,4H), 3.24-3.09 (m, 4H), 2.55 (s, obscured in part by solvent signal,3H), MS (posESI) m/z=382 (M+H).

Example 453,4-Dichloro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

MS (posESI) m/z=436 (M+H)

Example 465-Bromo-2-methoxy-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 10.13 (s, 1H), 9.10 (brs, 2H), 8.16-8.07 (m, 2H),7.78-7.71 (m, 1H), 7.59 (d, J=2.64 Hz, 1H), 7.57-7.46 (m, 2H), 7.22-7.06(m, 3H), 3.19 (s, 3H), 3.40-3.30 (m, obscured by solvent signal),3.24-3.09 (m, 4H), MS (posESI) m/z=476 (M+H).

Example 472-Bromo-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 9.37 (brs, 1H), 8.22-8.07 (m, 2H), 7.89-7.79 (m,2H), 7.57-7.40 (m, 4H), 7.05 (s, 2H), 3.40-3.30 (m, obscured by solventsignal), 3.24-3.09 (m, 4H), MS (posESI) m/z=446 (M+H).

Example 483-Chloro-2-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 9.11 (brs, 1H), 8.17-8.09 (m, 1H)), 8.04-7.96 (m,1H), 7.73-7.67 (m, 2H), 7.58-7.46 (m, 2H), 7.36-7.27 (m, 1H), 7.11-6.99(m, 2H), 3.40-3.30 (m, obscured by solvent signal), 3.24-3.09 (m, 4H),2.57 (s, 3H), MS (posESI) m/z=416 (M+H).

Example 492,6-Dichloro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 10.60 (s, 1H), 9.08 (brs, 1H), 8.18-8.06 (m, 2H),7.66-7.44 (m, 5H), 7.09 (s, 2H), 3.40-3.30 (m, obscured by solventsignal), 3.24-3.09 (m, 4H), MS (posESI) m/z=436 (M+H).

Example 503-Methoxy-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 10.13 (s, 1H), 9.07 (brs, 2H), 8.15-8.08 (m, 1H),8.02-7.95 (m, 1H), 7.56-7.36 (m, 3H), 7.28-7.22 (m, 1H), 7.19-7.02 (m,4H), 3.69 (s, 3H), 3.40-3.30 (m, 4H), 3.24-3.10 (m, 4H), MS (posESI)m/z=398 (M+H).

Example 513-Chloro-4-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 10.20 (brs, 1H), 9.12 (brs, 2H), 8.16-8.10 (m, 1H),8.04-7.97 (m, 1H), 7.65-7.61 (m, 1H), 7.58-7.43 (m, 4H), 7.12-6.99 (m,2H), 3.40-3.30 (m, obscured by solvent signal), 3.24-3.09 (m, 4H), 2.36(s, 3H), MS (posESI) m/z=416 (M+H).

Example 524-Bromo-2-fluoro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 10.59 (s, 1H), 9.17 (brs, 2H), 8.17-8.09 (m, 1H),8.08-7.99 (m, 1H), 7.87-7.80 (m, 1H), 7.59-7.46 (m, 4H), 7.16-7.07 (m,2H), 3.42-3.28 (, 4H), 3.24-3.08 (m, 4H), MS (posESI) m/z=464 (M+H).

Example 532,4-Dichloro-6-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 9.08 (brs, 2H), 8.18-8.04 (m, 2H), 7.73-7.69 (m,1H), 7.60-7.42 (m, 3H), 7.14-7.04 (m, 2H), 3.40-3.30 (m, obscured bysolvent signal), 3.24-3.09 (m, 4H), 2.80 (s, 3H), MS (posESI) m/z=450(M+H).

Example 544-Bromo-2-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 10.24 (brs, 1H), 9.12 (brs, 2H), 8.17-8.10 (m, 1H),8.05-7.98 (m, 1H), 7.68-7.65 (m, 1H), 7.58-7.46 (m, 4H), 7.10-6.96 (m,2H), 3.40-3.30 (m, obscured by solvent signal), 3.24-3.09 (m, 4H), 2.53(s, obscured in part by solvent signal, 3H), MS (posESI) m/z=450 (M+H).

Example 55 4,5-Dichloro-thiophene-2-sulfonic acid(4-piperazin-1-yl-naphthalen-1-yl)-amide, hydrochloride

¹H NMR (DMSO-d6) δ; 8.97 (brs, 2H), 8.19-8.12 (m, 1H), 8.01-7.94 (m,1H), 7.60-7.47 (m, 2h), 7.50 (S, 1H), 7.25-7.14 (m, 2H), 3.40-3.30 (m,obscured by solvent signal), 3.24-3.09 (m, 4H), MS (posESI) m/z=442(M+H).

Example 56N-Methyl-N-(4-bromo-2-methylphenyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide,hydrochloride

¹H NMR (DMSO) δ 9.39 (br s, 2H), 8.23-8.13 (m, 1H), 8.09-7.99 (m, 1H),7.75-7.56 (m, 5H), 7.13-7.02 (m, 2H), 3.41-3.18 (m, 8H), 3.26 (s, 3H),2.25 (s, 3H); MS m/z (M+1) 475.

Example 57N-Methyl-N-(5-fluoro-2-methylphenyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide,hydrochloride

¹H NMR (DMSO) δ 9.21 (br s, 2H), 8.23-8.14 (m, 1H), 8.04-7.97 (m, 1H),7.64-7.45 (m, 5H), 7.13-7.03 (m, 2H), 3.43-3.17 (m, 8H), 3.29 (s, 3H),2.21 (s, 3H); MS m/z (M+1) 414.

Example 58N-Methyl-N-(2-methylphenyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide,hydrochloride

¹H NMR (CD₃OD) δ 8.26-8.19 (m, 1H), 8.11-8.05 (m, 1H), 7.87-7.81 (m,1H), 7.62-7.49 (m, 3H), 7.40-7.32 (m, 2H), 7.13-7.03 (m, 2H), 3.57-3.49(m, 4H), 3.34-3.30 (m, 7H), 2.30 (s, 3H); MS m/z (M+1) 396.

Example 59N-Methyl-N-(3-chloro-2-methylphenyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide,hydrochloride

¹H NMR (DMSO) δ 9.52 (br s, 2H), 8.23-8.14 (m, 1H), 8.04-7.96 (m, 1H),7.88-7.76 (m, 2H), 7.64-7.54 (m, 2H), 7.49-7.39 (m, 1H), 7.17-7.05 (m,2H), 3.42-3.16 (m, 8H), 3.27 (s, 3H), 2.34 (s, 3H); MS m/z (M+1) 430.

Example 602,5-Dichlorothiophen-3-yl-Methyl-N-(2,5-dichlorothiophen-3-yl)-4-(1-pyperazinyl)-1-napthalenesulphonamide,hydrochloride

¹H NMR (DMSO) δ 9.49 (br s, 1H), 8.24-8.13 (m, 1H), 8.07-7.98 (m, 1H),7.67-7.55 (m, 2H), 7.33 (s, 1H), 7.24-7.07 (m, 2H), 3.44-3.18 (m, 10H);MS m/z (M+1) 456.

Example 61N-Methyl-N-(1-naphthyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide,hydrochloride

The compound was prepared1-tert-butyl-4-(4-{bis[(2-naphthalene)sulfonyl]amino}-1-naphthyl)-1-piperazinecarboxylateand potassium carbonate (120 mg, 0.87 mmol) in acetone (2 ml) was addediodomethane (44 μl, 0.7 mmol) and the mixture was stirred at roomtemperature over night. The mixture was diluted with acetonitrile,filtered and concentrated in vacuo. The residue was redissolved in DCM(3 ml) and treated with concentrated TFA (1 ml) at 0° C. for 30 min andthen allowed to reach room temperature. Removal of the solvents in vacuoand purification by reversed phase HPLC. followed by treatment of theresidue with an excess of 1M HCl in diethyl ether, gave the titlecompound (70 mg, 58%) as a solid. ¹H NMR (DMSO) δ 9.28 (br s, 2H), 8.44(s, 1H), 8.24-8.07 (m, 5H), 7.80-7.56 (m, 5H), 7.07-7.00 (m, 1H),6.88-6.81 (m, 1H), 3.41-3.18 (m, 8H), 3.27 (s, 3H); MS m/z (M+1) 432.

Example 62N-Methyl-N-(1-naphthyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide,hydrochloride

¹H NMR (DMSO) δ 9.25 (br s, 2H), 8.37-8.28 (m, 2H), 8.22-8.08 (m, 3H),8.02-7.95 (m, 1H), 7.72-7.46 (m, 5H), 6.97 (s, 2H), 3.42-3.33 (m, 4H),3.25 (s, 3H), 3.24-3.16 (m, 3H); MS m/z (M+1) 432.

Example 63N-Methyl-N-(4-chlorophenyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide,hydrochloride

¹H NMR (DMSO) δ 9.41 (br s, 2H), 8.23-8.05 (m, 2H), 7.73 (s, 4H),7.67-7.56 (m, 2H), 7.13-7.03 (m, 1H), 6.92-6.85 (m, 1H), 3.42-3.19 (m,8H), 3.22 (s, 3H); MS m/z (M+1) 416.

Example 64N-Methyl-N-(4-methoxyphenyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide,hydrochloride

¹H NMR (DMSO) δ 9.45 (br s, 2H), 8.22-8.11 (m, 2H), 7.69-7.57 (m, 4H),7.21-7.14 (m, 2H), 7.09-7.03 (m, 1H), 6.86-6.81 (m, 1H), 3.87 (s, 3H),3.41-3.19 (m, 8H), 3.16 (s, 3H); MS m/z (M+1) 412.

Example 655-Fluoro-2-methyl-N-{4-[(2R,5S)-2,5-dimethyl-1-]piperazin-1-yl-1-naphthyl}benzenesulfonamide,hydrochloride

Synthesis of (2R,5S)-Z 5-Dimethyl-1-(4-nitro-1-naphthyl)piperazine—Amixture of 1-chloro-4-nitronaphtalene (400 mg, 1.9 mmol),(2R,5S)-2,5-dimethylpiperazine (800 mg, 7 mmol) and potassium carbonate(1 g, 7 mmol) in DMSO (4 ml) was stirred at 100° C. over night followedby an additional 48 hours at room temperature. The reaction mixture wasdiluted with ethyl acetate and filtered. The filtrate was washed withbrine and 2M NaOH solution and then dried with potassium carbonate. Theresidue was purified on a silica column, using 10% methanol inchloroform as an eluent, to give the title compound (220 mg, 41%) as anoil. ¹H NMR (CDCl₃) δ 8.68-8.53 (m, 2H), 8.31-8.26 (m, 1H), 7.76-7.59(m, 2H), 7.30-7.24 (m, 1H), 3.32-3.87 (m, 4H), 2.96-2.82 (m, 1H),2.44-2.32 (m, 1H), 1.14-1.04 (m, 3H), 0.99-0.89 (m, 3H); MS m/z (M+1)286.

Synthesis of tert-Butyl(2R,5S)-2,5-dimethyl-1-(4-nitro-1-naphthyl)piperazine-1-carboxylate—To astirred solution of(2R,5S)-2,5-Dimethyl-1-(4-nitro-1-naphthyl)piperazine (220 mg, 0.77mmol) in DCM (2 ml) was added, at 0° C., BOC-anhydride dissolved in DCM(2 ml). The solution was stirred for 15 min and was then allowed toreach room temperature. Water was added and the solution was extractedwith DCM. The organic phase was separated and dried with potassiumcarbonate to give the title compound (300 mg, 100%) as an oil. ¹H NMR(CDCl₃) δ 8.75-8.67 (m, 1H), 8.30-8.17 (m, 2H), 7.70-7.55 (m, 2H),6.93-6.86 (m, 1H), 4.60-4.50 (m, 1H), 3.97-3.65 (m, 4H), 2.90-2.73 (m,1H), 1.49 (s, 9H), 1.41-1.36 (m, 3H), 0.99-0.87 (m, 3H); MS m/z (M+1)386.

Synthesis of5-Fluoro-2-methyl-N-(4-[(2R,5S)-2,5-dimethyl-1-]piperazin-1-yl-1-naphthyl}benzenesulfonamidehydrochloride salt—A mixture of tert-butyl(2R,5S)-2,5-dimethyl-1-(4-nitro-1-naphthyl)piperazine-1-carboxylate (300mg, 0.78 mmol) and 10% Pd on carbon (approx. 0.1 mmol) in methanol (10ml) was stirred in an hydrogen atmosphere over night. The mixture wasfiltered through a pad of Celite and the solvent evaporated. The crudeaniline was dissolved in DCM (2 ml) and pyridine (0.5 ml) and5-fluoro-2-methylbenzenesulfonyl chloride (97 μl, 0.67 mmol) was addedslowly to the solution. After stirring for 2 hours water was added andthe solution was extracted with DCM, the organic phase separated anddried using potassium carbonate. Removal of the solvents in vacuo gave aresidue which was dissolved in DCM (3 ml) and treated with concentratedTFA (2 ml) at 0° C. The stirred solution was allowed to reach roomtemperature after which the solvents where removed in vacuo to give,after purification by reversed phase HPLC and treatment with an excessof 1M HCl in diethyl ether, the title compound (30 mg, 9%) as a solid.¹H NMR (CD₃OD) δ 0.85 (d, J=6.07 Hz, 3H) 1.31 (d, J=6.60 Hz, 3H) 2.47(s, 3H) 2.83 (m, 1H) 3.15 (m, 2H) 3.49 (m, 2H) 3.67 (m, 1H) 7.21 (m, 4H)7.47 (m, 3H) 7.97 (m, J=7.92 Hz, 1H) 8.44 (d, J=8.44 Hz, 1H) MS m/z 428(M+1).

Example 665-Fluoro-2-methyl-N-[4-(1,2,3,6-tetrahydropyridin-4-yl)-1naphthyl]benzenesulfonamide,hydrochloride

5-Fluoro-2-methyl-N-[4-bromo-1-naphthyl]benzenesulfonamide—4-Bromo-1-naphthylamine(0.96 g, 4.33 mmol) was dissolved in DCM (10 mL) before pyridine (1 mL)was added. 5-Fluoro-2-methylbenzenesulfonyl chloride was added neat andthe reaction mixture was stirred for 16 h. HCl (1 M, 1 mL) was added tothe reaction mixture. The organic phase was filtered through a Silicaplug using DCM as eluent. The solvent was evaporated. The obtained crudeproduct was purified by flash-chromatography using MeOH (10%) inpentane, to give the desired product as a tar. To increase the purity,the product was purified by recrystallising (EtOAc/hexanes). This gavethe product with a purity of 95%. ¹H NMR (270 MHz, CDCl₃) δ 8.22 (d,J=8.98 Hz, 1H), 7.92 (d, J=7.92 Hz, 1H), 7.64-7.51 (m, 4H), 7.25-7.23(m, 1H), 7.21-7.05 (m, 2H), 6.84 (br.s, 1H, N—H), 2.55 (s, 3H); MS(ESI+) for C17 H13 Br F N O2 S m/z 394.263 (M+H)⁺.

MS (ESI−) for C17 H13 Br F N O2 S m/z 394.263 m/z (M−H)⁻.

5-Fluoro-2-methyl-N-[4-(4-(tert-butoxycarbonyl)-1-hydroxypiperidin-1-yl)-1-naphthyl]benzenesulfonamide—5-Fluoro-2-methyl-N-[4-bromo-1-naphthyl]benzenesulfonamide(0.32 g, 0.812 mmol) was dissolved in dry THF (1 m mL) under N₂(g). Thereaction flask was cooled to −78° C. before n-BuLi (1.5 mL, 2.4 mmol)was added. The reaction mixture turned green. The reaction mixture wasstirred for 5 minutes before a solution of tert-butyl4-oxopiperidine-1-carboxylate (0.34 g, 1.7 mmol) was added during 10 s.The resulting reaction mixture was stirred and slowly reaching −30° C.after 3 h. Water dissolved in THF was added and the reaction flask wasbrought to RT. Brine and EtOAc was added. The phases were separated andthe organic phase was dried (MgSO4). The obtained crude product waspurified by reverse-phase (using the gradient 40→90). This gave 0.17 gof the desired product. Purity 95%. ¹H NMR (270 MHz, CDCl₃) δ 8.91-8.87(m, 1H), 7.97-7.93 (m, 1H), 7.63-7.59 (m, 1H), 7.53-7.45 (m, 2H), 7.35(d, J=8.1 Hz, 1H), 7.28-7.21 (m, 1H), 7.16-7.09 (m, 2H), 7.14 (br.s, 1H,N—H), 6.85 (br.s, 1H, O—H), 4.07-3.98 (m, 2H), 3.41-3.31 (m, 2H), 2.59(s, 3H), 2.17-2.08 (m, 4H), 1.46 (s, 9H); MS (ESI+) for C27 H31 F N2 O5S m/z 514.615 (M+H)⁺. Nothing; MS (ESI−) for C27 H31 F N2 O5 S m/z514.615 (M−H)⁻ 513.1.

The final product was obtained as following:5-Fluoro-2-methyl-N-[4-(4-(tert-butoxycarbonyl)-1-hydroxypiperidin-1-yl)-1-naphthyl]benzenesulfonamide(0.022 g, 0.043 mmol) was dissolved in formic acid (5 mL) and stirred atRT for 24 h. HPLC showed complex reaction mixture. The reaction mixturewas stirred at 100° C. for 4 h. One compound was seen on HPLC. Thesolvent was evaporated. The crude was transformed to the HCl salt (0.020g) for the desired product, purity 98%. ¹H NMR (270 MHz, CD₃OD) δ8.05-7.97 (m, 2H), 7.55-7.43 (m, 3H), 7.33-7.30 (m, 1H), 7.24-7.17 (m,3H), 5.97 (br.s, 1H), 3.90-3.88 (m, 2H), 3.56-3.52 (m, 2H), 2.73-2.70(m, 2H), 2.53 (s, 3H); MS (ESI+) for C22 H21 F N2 O2 S HCl m/z396.13+35.98 (M+H)⁺ 397.2; MS (ESI−) C22 H21 F N2 O2 S HCl m/z396.13+35.98 (M−H)⁻. 395.3.

Synthesis of Example in Table II Example 67N-[4-(4-Methyl-1-piperazinyl)-2-naphthyl]benzenesulfonamide,hydrochloride

To a solution of 1-(4-dimethyl-1-piperazinyl)-3-naphthylamine (0.230 g,0.951 mmol) and pyridine (537 μL, 6.66 mmol) in DCM (3.0 mL) was addedbenzenesulfonyl chloride (0.168 g, 0.951 mmol) in DCM (1.01 mL). Thereaction mixture was stirred at room temperature for 16 hours and thenand then concentrated. The crude intermediate was first purified viacolumn chromatography on silica using CHCl₃/CHCl₃+10% MeOH+0.4% NH₃ andthen by preparative HPLC to give the pure base which was converted toits HCl-salt (yield 53% as HCl-salt): 1H NMR (DMSO-d6) δ 10.76 (br s,1H), 10.50 (s, 1H), 7.98-7.94 (m, 1H), 7.85-7.81 (m, 2H), 7.76-7.73 (m,1H), 7.60-7.56 (m, 1H), 7.55-7.51 (m, 2H), 7.30 (d, J=1.60 Hz, 1H), 6.99(d, J=1.88 Hz, 1H), 3.58-3.48 (m, 2H), 3.42-3.25 (m, m, partly obscuredby HDO signal, 4H), 3.12-3.00 (m, 2H), 2.86 (s, 3H); MS (posES-FIA)m/z=381.15 24 (M+H)(calc 381.1511)

Synthesis of Intermediates and Examples in Table III

In scheme 2, the following reagents are used: (i) Chlorosulphonic acid,trifluoroacetic acid; (ii) R¹—NH₂, pyridine (1:4); (iii) diamines ofchoice and DMSO.Intermediate 16

4-Fluoro-naphthalene-1-sulfonyl chloride—An emulsion of1-fluoronaphthalene (4.00 g, 27 mmol) in TFA (19.5 mL) was stirred on anice-bath. Chlorosulfonic acid (4.33 mL, 65 mmol) was added dropwise over30 min. The ice-bath was removed and the reaction slurry stirred at rtfor 2 h. Pouring the reaction mixture on 29 mL ice-cold water gave awhite precipitate, which was filtered and washed with cold water. Afterdrying, 4.50 g of white solid (67%): ¹H NMR (CDCl₃, 400 MHz) δ 8.80 (d,1H), 8.39 (dd, 1H), 8.28 (d, 1H), 7.88 (t, 1H), 7.76 (t, 1H), 7.26 (t,1H); MS (EI) 244 (M). Purity (HPLC, Hichrom 200×4.6 mm I.D.)>98%.

General Method C

4-Fluoro-naphthalene-1-sulfonic acid phenylamide,4-fluoro-naphthalene-1-sulfonic acid (2-methoxy-phenyl)-amide and4-fluoro-naphthalene-1-sulfonic acid (3-chloro-phenyl)-amide—Threereaction flasks with 4-fluoro-naphthalene-1-sulfonyl chloride (489 mg,2.00 mmol) in CH₂Cl₂ (2 mL) were treated with aniline (224 mg, 2.40mmol), o-anisidine (296 mg, 2.40 mmol) and m-chloroaniline (306 mg, 2.40mmol), respectively. Pyridine (0.5 mL) was added and the reactionmixtures stirred for 3 h at rt. Dilution with ethyl acetate (50 mL)followed by washing with 1 M HCl (3×50 mL), drying (Na₂SO₄) andevaporation gave 586 mg of 4-fluoro-naphthalene-1-sulfonic acidphenylamide (97%), 629 mg of 4-fluoro-naphthalene-1-sulfonic acid(2-methoxy-phenyl)-amide (95%) and 656 mg of and4-fluoro-naphthalene-1-sulfonic acid (3-chloro-phenyl)-amide (97%) aspink to red solids.

Intermediate 17

4-Fluoro-naphthalene-1-sulfonic acid phenylamide: ¹H NMR (CDCl₃, 400MHz) δ 8.66 (d, 1H), 8.20 (d, 1H), 8.15 (dd, 1H), 7.74 (t, 1H), 7.66 (t,1H), 7.03-7.15 (m, 4H), 6.89 (d, 2H), 6.60 (bs, 1H); MS (CI) 299.8(M−H)⁺; Purity (HPLC, Hichrom 200×4.6 mm I.D.)>98%.

Intermediate 18

4-Fluoro-naphthalene-1-sulfonic acid (2-methoxy-phenyl)-amide: ¹H NMR(CDCl₃, 400 MHz) δ 8.70 (d, 1H), 8.16 (d, 1H), 8.12 (dd, 1H), 7.71 (t,1H), 7.63 (t, 1H), 7.42 (d, 1H), 7.16 (bs, H), 7.06 (t, 1H), 6.95 (t,1H), 6.83 (t, 1H), 6.56 (d, 1H), 3.30 (s, 3H); MS (CI) 330.2 (M−H)⁺;Purity (HPLC, Hichrom 200×4.6 mm I.D.)>98%.

Intermediate 19

4-Fluoro-naphthalene-1-sulfonic acid (3-chloro-phenyl)-amide: ¹H NMR(CDCl₃, 400 MHz) δ 8.64 (d, 1H), 8.18-8.22 (m, 2H), 7.76 (t, 1H), 7.68(t, 1H), 7.14 (dd, 1H), 7.06 (t, 1H), 7.02 (d, 1H), 6.97 (t, 1H), 6.78(d, 1H), 6.67 (bs, 1H); MS (CI) 334.2 (M−H)⁺; Purity (HPLC, Hichrom200×4.6 mm I.D.)>98%.

General Procedure D

General Procedure for Preparation of Compounds According to Examples68-74:

Solutions of 4-fluoro-naphthalene-1-sulfonic acid(2-methoxy-phenyl)-amide (60 mg, 0.20 mmol),4-fluoro-naphthalene-1-sulfonic acid (2-methoxy-phenyl)-amide (66 mg,0.20 mmol) and 4-fluoro-naphthalene-1-sulfonic acid(3-chloro-phenyl)-amide (67 mg, 0.20 mmol) in DMSO (2 mL) were treatedwith piperazine (86 mg, 1.0 mmol), homopiperazine (100 mg, 1.0 mmol) andcis-2,6-dimethyl piperazine (114 mg, 1.0 mmol) in eight reactioncombinations. The reaction mixtures were stirred at 100° C. for 3 h,diluted with ethyl acetate (50 mL), washed with sat. Na₂CO₃ (3×50 mL),dried (Na₂SO₄) and evaporated with an excess of HCl in ether, giving thehydrochlorides. No purification was necessary for compounds 20-23, whilecompounds 24-27 were purified with HPLC (YMC combiprep ODS-AQ, 50×20 mmI.D.).

Example 68 4-piperazin-1-yl-naphthalene-1-sulfonic acid phenylamide,hydrochloride

86 mg (95% yield) of a white solid. ¹H NMR (DMSO, 400 MHz) δ 9.52 (bs,1H), 8.72 (d, 1H), 8.20 (d, 1H), 8.15 (d, 1H), 7.71 (t, 1H), 7.64 (t,1H), 7.20 (d, 1H), 7.13 (t, 2H), 7.01 (d, 2H), 6.90 (t, 1H), 3.35 (bs,4H), 3.30 (bs, 4H). ¹³C NMR (DMSO, 101 MHz) δ 153.3, 137.7, 137.6,130.8, 129.2, 129.0, 128.9, 127.9, 126.5, 124.9, 124.5, 123.3, 118.7,113.0, 49.1, 42.8; MS (CI) 368.0 (M+H)⁺, 366.4 (M−H)⁻; Purity (HPLC,Hichrom 200×4.6 mm I.D.) 90%.

Example 69 4-piperazin-1-yl-naphthalene-1-sulfonic acid(2-methoxy-phenyl)-amide, hydrochloride

¹H NMR (DMSO, 400 MHz) δ 9.59 (s, 1H), 8.76 (d, 1H), 8.23 (d, 1H), 7.93(d, 1H), 7.64-7.70 (m, 2H), 7.14-7.19 (m, 2H), 7.05 (t, 1H), 6.82 (t,1H), 6.76 (d, 1H), 3.39 (bs, 4H), 3.29 (bs, 4H), 3.11 (s, 3H). ¹³C NMR(DMSO, 101 MHz) δ 152.9, 152.5, 130.6, 129.7, 129.3, 127.9, 127.3,126.5, 126.3, 125.7, 125.3, 125.2, 124.1, 120.2, 112.8, 111.6, 54.9,49.2, 43.0. MS (CI) 398.2 (M+H)⁺, 396.2 (M−H)⁻; Purity (HPLC, Hichrom200×4.6 mm I.D.) 96%.

Example 70 4-(cis-3,5-Dimethyl-piperazin-1-yl)-naphthalene-1-sulfonicacid (2-methoxy-phenyl)-amide, hydrochloride

¹H NMR (DMSO, 400 MHz) δ 9.75-9.81 (m, 1H), 9.60 (s, 1H), 9.03-9.12 (m,1H), 8.76 (d, 1H), 8.23 (d, 1H), 7.93 (d, 1H), 7.64-7.71 (m, 2H), 7.05(t, 1H), 6.82 (t, 1H), 6.76 (d, 1H), 3.63-3.71 (m, 2H), 3.47 (d, 2H),3.13 (s, 3H), 2.89 (t, 2H), 1.32 (d, 6H). ¹³C NMR (DMSO, 101 MHz) δ152.4, 152.3, 130.6, 129.8, 129.3, 127.9, 127.3, 126.5, 126.3, 125.3,125.2, 125.1, 124.1, 120.2, 113.0, 111.6, 55.0, 54.9, 51.2, 15.5. MS(CD) 426.2 (M+H)⁺, 424.4 (M−H)⁻; Purity (HPLC, Hichrom 200×4.6 mm I.D.)96%.

Example 71 4-(cis-3,5-Dimethyl-piperazin-1-yl)-naphthalene-1-sulfonicacid (3-chloro-phenyl)-amide, hydrochloride

¹H NMR (MeOD, 400 MHz) δ 8.80 (d, 1H), 8.32 (d, 1H), 8.27 (d, 1H), 7.79(t, 1H), 7.73 (t, 1H), 7.28 (d, 1H), 7.12 (t, 1H), 7.07 (t, 1H),6.95-7.00 (m, 2H); MS (CI) 430.2 (M+H)⁺, 428.4 (M−H)⁻; Purity (HPLC,Hichrom 200×4.6 mm I.D.) 98%.

Example 72 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid(3-chloro-phenyl)-amide, hydrochloride

¹H NMR (MeOD, 400 MHz) δ 8.69 (d, 1H), 8.28 (d, 1H), 8.14 (d, 1H), 7.68(t, 1H), 7.61 (t, 1H), 7.22 (d, 1H), 7.02 (t, 1H), 6.97 (bs, 1H),6.86-6.89 (m, 2H), 3.57 (bs, 2H), 3.48 (bs, 4H), 3.33-3.37 (m, 2H),2.20-2.24 (m, 2H); MS (CI) 416.0 (M+H)⁺, 414.2 (M−H)⁻; Purity (HPLC,Hichrom 200×4.6 mm I.D.) 88%.

Example 73 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid phenylamide,hydrochloride

¹H NMR (MeOD, 400 MHz) δ 8.57 (d, 1H), 8.13 (d, 1H), 7.96 (d, 1H),7.44-7.55 (m, 2H), 7.04 (d, 1H), 6.90 (t, 2H), 6.72-6.82 (m, 3H),3.39-3.43 (m, 2H), 3.32-3.36 (m, 4H), 3.17-3.21 (m, 2H), 2.05-2.10 (m,2H); MS (CI) 382.2 (M+H)⁺, 380.4 (M−H)⁻; Purity (HPLC, Hichrom 200×4.6mm I.D.) 94%.

Example 74 4-piperazin-1-yl-naphthalene-1-sulfonic acid(3-chloro-phenyl)-amide, hydrochloride

¹H NMR (MeOD, 400 MHz) δ 8.69 (d, 1H), 8.23 (d, 1H), 8.16 (d, 1H), 7.68(t, 1H), 7.62 (t, 1H), 7.17 (d, 1H), 7.02 (t, 1H), 6.97 (t, 1H),6.85-6.89 (m, 2H), 3.46-3.50 (m, 4H), 3.33 (bs, 4H); MS (CI) 402.2(M+H)⁺, 400.0 (M−H)⁻; Purity (HPLC, Hichrom 200×4.6 mm I.D.) 98%.

4-Fluoro-naphtalene-1-sulfonylchloride was dissolved in DCM. The amine(1.2 eq) was added followed by pyridine (3 eq). The mixture was stirredfor 2 h at ambient temperature, diluted with DCM and washed 2 times withHCl (1M). The organic layer was filtered through a silica plug to affordthe sulfonylamide.

The sulfonamide and the amine (5 eq) were dissolved in DMSO and stirredat 100° C. overnight. The DMSO solution was added dropwise to water togive a precipitate. After centrifugation, the solvent was decanted andthe procedure was repeated. The residue was dissolved in MeOH andconverted to HCl salt by adding HCl in ether (2 M) and evaporation.

To a solution of the sulfonamide in acetone, K₂CO₃ (3 eq) was addedfollowed by MeI (1.2 eq). The mixture was stirred overnight, filteredthrough a short silica plug and evaporated to give the methylatedsulfonamide.

Example 75 4-piperazin-1-yl-naphthalene-1-sulfonic acid(2-methylsulfanyl-phenyl)-amide, hydrochloride

N-(2-methylsulfanyl-phenyl)-4-fluorosulphonamide—Method E; Yield (84%)

¹H NMR (CDCl₃) δ 8.74-8.70 (m, 1H), 8.29-8.24 (m, 1H), 8.17-8.14 (m, 1H), 8.01 (br. s, 1H), 7.75-7.60 (m, 2H), 7.50-7.47 (m, 1H), 7.29-7.25 (m,1H), 7.18-7.10 (m, 2H), 6.98-6.92 (m, 1H), 2.02 (s, 3H); MS (ESI+) forC17 H14 F N O2 S2 m/z 348 (M+H)⁺.

The final product was prepared according to Method F; Yield 0.77 g (53%)

¹H NMR (DMSO-d₆) δ 11.13 (s, 1H), 9.42 (br. s, 2H), 8.69-8.66 (m, 1H),8.21-8.18 (m, 2H), 7.76-7.62 (m, 2H), 7.42-7.21 (m, 5H), 3.421-3.30 (m,8H); MS (ESI+) for C21 H23 N3 O2 S2 m/z 414.2 (M+H)⁺.

Example 76 4-piperazin-1-yl-naphthalene-1-sulfonic acidmethyl-naphthalen-1-yl-amide, hydrochloride

N-(1-naphthyl)-4-fluoronaqphthalensulphonamide—Method E; Yield (83%)

¹H NMR (CDCl₃) δ 8.77-8.74 (m, 1H), 8.18-8.05 (m, 2H), 7.75-7.61 (m,5H), 7.41-7.35 (m, 1H), 7.30-7.26 (m, 1H), 7.14-7.00 (m, 2H), 6.93 (br.s, 1H); MS (ESI+) for C20 H14 F N O2 S m/z 352 (M+H)⁺.

4-Fluoro-1-naphthalene-1-sulfonic acidmethyl-naphthalen-1-yl-amide—Methylation according to Method G, Yield(97%)

¹H NMR (DMSO-d₆) δ 8.38-8.35 (m, 1H), 8.23-8.20 (m, 1H), 8.16 (dd,J=8.4, 5.5 Hz, 1H), 7.99-7.91 (m, 3H), 7.79-7.73 (m, 1H), 7.66-7.46 (m,4H), 7.37-7.31 (m, 1H), 7.03 (dd, J=7.5, 1.2 Hz, 1H), 3.29 (s, 3H)

The final product was prepared according to Method F; Yield (36%)

¹H NMR (DMSO-d₆) δ 9.33 (br. s, 1H), 8.40 (d, J=8.4 Hz, 1H), 8.25 (d,J=7.9 Hz, 1H), 8.09 (d, J=8.2 Hz, 1H), 7.98-7.91 (m, 3H), 7.68-7.62 (m,1H), 7.58-7.43 (m, 3H), 7.40-7.34 (m, 1H), 7.24 (d, J=8.2 Hz, 1H),7.13-7.10 (m, 1H), 3.44-3.39 (m, 4H), 3.29 (br. s, 4H), 3.25 (s, 3H); MS(ESI+) for C25 H25 N3 O2 S m/z 432 (M+H)⁺.

Example 77 4-piperazin-1-yl-naphthalene-1-sulfonic acid(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methyl-amide, hydrochloride

N-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-4-sulphonamide—Method E; Yield(96%). ¹H NMR (CDCl₃) δ 8.66-8.63 (m, 1H), 8.22-8.09 (m, 2H), 7.77-7.63(m, 2H), 7.10 (dd, J=8.2, 9.5 Hz, 1H), 6.58 (d, J=8.5 Hz, 1H), 6.46 (d,J=2.4 Hz, 1H), 6.30 (dd, J=2.6, 8.7 Hz, 1H), 4.14 (s, 4H); MS (ESI+) forC18 H14 F N O4 S m/z 360 (M+H)⁺.

4-Fluoro-Nl-naphthalene-1-sulfonicacid-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methyl-amide—Methylationaccording to Method G; Yield (100%). ¹H NMR (DMSO-d₆) δ 8.19-8.13 (m,2H), 8.09 (dd, J=8.4, 5.5 Hz, 1H), 7.75-7.70 (m, 1H), 7.64-7.58 (m, 1H),7.50 (dd, J=10.0, 8.4 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 6.55 (d, J=2.6Hz, 1H), 6.51-6.47 (m, 1H), 4.20-4.15 (m, 4H), 3.10 (s, 3H)

The final product was prepared according to Method F; the productprecipitates in MeOH; Yield (57%): ¹H NMR (DMSO-d₆) δ 9.29 (br. s, 2H),8.23-8.16 (m, 2H), 8.01 (d, J=8.2 Hz, 1H), 7.64-7.49 (m, 2H), 7.25 (d,J=8.2 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 6.56-6.48 (m, 2H), 4.21-4.16 (m,4H), 3.38-3.31 (m, 4H), 3.08 (s, 3H); MS (ESI+) for C23 H25 N3 O4 S m/z440 (M+H)⁺.

Example 78 4-piperazin-1-yl-naphthalene-1-sulfonic acid(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide, hydrochloride

The final product was prepared according to Method F; Yield (36%); ¹HNMR (270 MHz, DMSO-D6) δ ppm 3.32 (m, 8H) 4.08 (m, 4H) 6.45 (m, 2H) 6.61(d, J=8.44 Hz, 1H) 7.20 (d, J=8.18 Hz, 1H) 7.67 (m, 2H) 8.07 (d, J=7.92Hz, 1H) 8.21 (d, J=8.71 Hz, 1H) 8.67 (d, J=8.44 Hz, 1H) 9.22 (s, 1H)10.32 (s, 1H); MS (ESI+) for C22 H23 N3 O4 S m/z 426.2 (M+H)⁺.

Example 79 4-piperazin-1-yl-naphthalene-1-sulfonic acidmethyl-(2-methylsulfanyl-phenyl)-amide, hydrochloride

4-Fluoro-N-methyl-N-(2-methylsulfanyl-phenyl)-amide—Methylationaccording to Method G; Yield (97%); ¹H NMR (DMSO-d₆) δ 8.52-8.49 (m,1H), 8.22-8.19 (m, 1H), 8.16 (dd, J=8.4, 5.5 Hz, 1H), 7.79-7.66 (m, 2H),7.52 (dd, J=10.0, 8.4 Hz, 1H), 7.37-7.24 (m, 2H), 7.06-7.00 (m, 1H),6.88 (dd, J=7.9, 1.3 Hz, 1H), 3.10 (s, 3H), 2.28 (s, 3H).

The final product was prepared according to Method F; Trituration withMeCN; Yield (65%) ¹H NMR (DMSO-d₆) δ 9.27 (br. s, 2H), 8.54-8.50 (m,1H), 8.27-8.23 (m, 1H), 8.09 (d, J=8.2 Hz, 1H), 7.67-7.56 (m, 2H),7.38-7.25 (m, 3H), 7.07-6.92 (m, 2H), 3.41-3.33 (m, 8H), 3.06 (s, 3H),2.30 (s, 3H); MS (ESI+) for C22 H25 N3 O2 S2 m/z 428 (M+H)⁺.

Example 80 4-piperazin-1-yl-naphthalene-1-sulfonic acidmethyl-(3-trifluoromethyl-phenyl)-amide, hydochloride

N-(3-trifluoromethylphenyl)-4-fluoronaphthalenesulphonamide—Method E;Yield (90%). ¹H NMR (CDCl₃) δ 8.65-8.62 (m, 1H), 8.23-8.18 (m, 2H),7.78-7.65 (m, 2H), 7.31-7.17 (m, 2H), 7.16-7.08 (m, 3H); MS (ESI+) forC17 H11 F4 N O2 S m/z 370 (M+H)⁺. Methylation according to Method F;Yield (100%); ¹H NMR (DMSO-d₆) δ 8.19-8.11 (m, 2H), 8.01-7.98 (m, 1H),7.73-7.62 (m, 2H), 7.57-7.44 (m, 4H), 7.35 (br. s, 1H), 3.21 (s, 3H).

The final product was prepared according to Method F; Trituration withMeCN; Yield 0.07 g (40%). ¹H NMR (DMSO-d₆) δ 9.35 (br. s, 2H), 8.21 (d,J=8.2 Hz, 1H), 8.06-8.02 (m, 2H), 7.63-7.42 (m, 5H), 7.28-7.24 (m, 2H),3.39 (br. s, 8H), 3.21 (s, 3H), 2.06 (s, 3H); MS (ESI+) for C22 H22 F3N3 O2 S m/z 450 (M+H)⁺.

Example 81 4-piperazin-1-yl-naphthalene-1-sulfonic acid(3-chloro-4-methyl-phenyl)-methyl-amide, hydrochloride

N-(3-Chloro-4-methylphenyl)-4-fluoronaphthalenesulphonamide—Method E;Yield (88%). ¹H NMR (DMSO-d₆) δ 10.86 (br. s, 1H), 8.74-8.71 (m, 1H),8.22 (dd, J=8.3, 5.4 Hz, 1H), 8.19-8.16 (m, 1H), 7.89-7.75 (m, 2H), 7.47(dd, J=10.0, 8.4 Hz, 1H), 7.12-7.09 (m, 1H), 7.00 (d, J=2.2 Hz, 1H),6.86 (dd, J=8.3, 2.2 Hz, 1H), 2.11 (s, 3H);

4-Fluoro-1-naphthalene-1-sulfonic acid(3-chloro-4-methyl-phenyl)-methyl-amide—Methylation according to MethodG; Yield (100%). ¹H NMR (DMSO-d₆) δ 8.20-8.07 (m, 3H), 7.76-7.70 (m,1H), 7.62-7.48 (m, 2H), 7.27-7.24 (m, 1H), 7.13 (d, J=2.4 Hz, 1H), 6.99(dd, J=8.2, 2.4 Hz, 1H), 3.15 (s, 3H), 2.28 (s, 3H);

The final product was prepared according to Method F; Yield (28%). ¹HNMR (DMSO-d₆) δ 9.29 (br. s, 2H), 8.24-8.15 (m, 2H), 8.01 (d, J=8.2 Hz,1H), 7.65-7.47 (m, 2H), 7.26 (dd, J=8.3, 4.6 Hz, 2H), 7.09-7.08 1H),7.03-6.99 (m, 1H), 3.38-3.33 (m, 8H), 3.14 (s, 3H), 2.27 (s, 3H); MS(ESI+) for C22 H24 Cl N3 O2 S m/z 430 (M+H)⁺.

Example 82 4-piperazin-1-yl-naphthalene-1-sulfonic acid(3-ethyl-phenyl)-methyl-amide, hydrochloride

N-(3-ethylphenyl)-4-fluoronaphthalenesulphonamide—Method E; Yield (85%).¹H NMR (CDCl₃) δ 8.66 (d, J=8.4 Hz, 1H), 8.20-8.14 (m, 2H), 7.75-7.62(m, 2H), 7.10 (dd, J=9.5, 8.4 Hz, 1H), 7.02 (t, J=7.8 Hz, 1H), 6.88-6.85(m, 1H), 6.72-6.68 (m, 3H), 2.45 (q, J=7.7 Hz, 2H), 1.03 (t, J=7.7 Hz,3H)

4-Fluoro-1-yl-naphthalene-1-sulfonic acid(3-ethyl-phenyl)-methyl-amide—Methylation according to Method G; Yield(100%); ¹H NMR (DMSO-d₆) δ 8.18-8.06 (m, 3 H), 7.72-7.66 (m, 1H),7.54-7.48 (m, 2H), 7.21-7.16 (m, 1H), 7.10-7.08 (m, 1H), 6.96-6.92 (m,1H), 6.81-6.80 (m, 1H), 3.16 (s, 3H), 2.41 (q, J=7.5 Hz, 2H), 0.93 (t,J=7.5 Hz, 3H)

The final product was prepared according to Method f; Trituration withMeCN; Yield (49%); ¹H NMR (DMSO-d₆) δ 9.21 (br. s, 2H), 8.21 (d, J=8.4Hz, 1H), 8.13 (d, J=8.7 Hz, 1H), 8.02 (d, J=8.2 Hz, 1H), 7.62-7.57 (m,1H), 7.47-7.41 (m, 1H), 7.27-7.17 (m, 2H), 7.10-6.95 (m, 2H), 6.8 (br.s, 1H), 3.40-3.29 (m, 8H), 3.15 (s, 3H), 2.43 (q, J=7.6 Hz, 2H), 0.95(t, J=7.6 Hz, 2H); MS (ESI+) for C23 H27 N3 O2 S m/z 410 (M+H)⁺.

Example 83 4-(3,5-Dimethyl-piperazin-1-yl)-naphthalene-1-sulfonic acid(2-isopropyl-phenyl)-amide, hydrochloride

The final product was prepared according to Method F; Yield (35%); ¹HNMR (270 MHz, DMSO-D6) δ ppm 0.64 (d, J=6.86 Hz, 6H) 1.30 (d, J=6.60 Hz,6H) 2.92 (m, 3H) 3.53 (m, 4H) 6.86 (d, J=7.65 Hz, 1H) 6.98 (m, 1H) 7.13(m, 3H) 7.67 (m, 2H) 7.86 (d, J=7.92 Hz, 1H) 8.24 (m, 1H) 8.74 (m, 1H)9.08 (m, 1H) 9.79 (m, 2H); MS (ESI+) for C25 H31 N3 O2 S m/z 438.01(M+H)⁺.

Example 84 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid(2-isopropyl-phenyl)-amide, hydrochloride

N-(2 isopropylphenyl)-4-fluoronaphthalensulphonamide—Method E; Yield(87%) ¹H NMR (CDCl₃) δ 8.67-8.64 (m, 1H), 8.22-8.18 (m, 1H), 8.12 (dd,J=8.3, 5.4 Hz, 1H), 7.71-7.62 (m, 2H), 7.15-6.97 (m, 5H), 2.84-2.73 (m,1H), 0.85 (s, 3H), 0.82 (s, 3H)

The final product was prepared according to Method F; Yield (22%). ¹HNMR (DMSO-d6) δ 9.83 (s, 1H), 9.37 (br. s, 2H), 8.74-8.70 (m, 1H),8.27.8.24 (m, 1H), 7.84 (d, J=7.9 Hz, 1H), 7.68-7.64 (m, 2H), 7.17-7.11(m, 3H), 7.01-6.87 (m, 2H), 3.82 (br. s, 6H), 3.51-3.50 (m, 2H),3.38-3.28 (m, 2H), 3.02-2.93 (m, 1H), 0.65 (s, 3H), 0.63 (s, 3H); MS(ESI+) for C24 H29 N3 O2 S m/z 424.02 (M+H)⁺.

Example 85 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid(3-ethyl-phenyl)-amide, hydrochloride

The final product was prepared according to Method F; Yield (22%); ¹HNMR (DMSO-d₆) δ 10.53 (s, 1H), 9.24 (br. s, 2H), 8.68 (d, J=8.2 Hz, 1H),8.20 (d, J=7.9 Hz, 1H), 8.14 (d, J=8.2 Hz, 1H), 7.72-7.60 (m, 2H), 7.22(d, J=8.2 Hz, 1H), 7.01 (t, J=7.8 Hz, 1H), 6.83-6.72 (m, 3H), 3.33 (br.s, 6H), 2.39 (q, J=7.7 Hz, 2H), 2.12 (br. s, 2H), is 0.98 (t, J=7.5 Hz,3H); MS (ESI+) for C23 H27 N3 O2 S m/z 410.03 (M+H)⁺.

Example 86 N-(2-Fluorophenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide,hydrochloride

N-(2-Fluorophenyl)-4-fluoronaphthalensulphonamide—Method E; Yield (88%);¹H NMR (DMSO-d₆) δ 10.41 (br. s, 1H), 8.76-8.69 (m, 1H), 8.20-8.17 (m,1H), 8.08 (dd, J=8.0, 5.5 Hz, 1H), 7.82-7.75 (m, 2H), 7.41 (dd, J=10.0,8.3 Hz, 1H), 7.20-7.01 (m, 4H); MS (ESI−) for C16 H11 F2 N O2 S m/z318.2 (M−H)⁻.

The final product was prepared according to Method F; Yield (22%); ¹HNMR (DMSO-d₆) δ 10.41 (s, 1H), 9.35 (m, 2H), 8.72-8.68 (m, 1H),8.24-8.20 (m, 1H), 8.02 (d, J=7.9 Hz, 1H), 7.72-7.62 (m, 2H), 7.22-7.00(m, 5H), 4.05 (d, J=1.3 Hz, 4H), 3.36 (s, 4H); MS (ESI+) for C20 H20 FN3 O2 S m/z 386 (M+H)⁺.

Example 87 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid(3-trifluoromethyl-phenyl)-amide, hydrochloride

The final product was prepared according to Method F; Yield (21%); ¹HNMR (DMSO-d6) δ 11.1 (s, 1H), 9.32 (br. s, 2H), 8.65 (d, J=8.2 Hz, 1H),8.19 (t, J=8.6 Hz, 2H), 7.75-7.62 (m, 2H), 7.42-7.22 (m, 4H), 3.88 (br.s, 6H), 3.55-3.53 (m, 2H), 2.11 (m, 2H); MS (ESI+) for C22 H22 F3 N3 O2S m/z 449.95 (M+H)⁺.

Example 88N-(2,4-difluorophenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide,hydrochloride

N-(2,4-di-Fluorophenyl)-4-fluoronaphthalensulphonamide—Method E; Yield(81%); ¹H NMR (DMSO-d₆) δ 10.44 (s, 1H), 8.73-8.69 (m, 1H), 8.21-8.18(m, 1H), 8.02 (dd, J=8.4, 5.5 Hz, 1H), 7.85-7.76(m, 2H), 7.41 (dd,J=10.2, 8.3 Hz, 1H), 7.22-7.11 (m, 2H), 7.01-6.93 (m, 1H); MS (ESI−) forC16 H10 F3 N O2 S m/z 336.2 (M−H)⁻.

The final product was prepared according to Method F; Yield (27%); ¹HNMR (DMSO-d6) δ 10.33 (s, 1H), 9.28 (br. s, 2H), 8.68-8.65 (m, 1H),8.25-8.21 (m, 1H), 8.0 (d, J=8.2 Hz, 1H), 7.73-7.62 (m, 2H), 7.21-7.08(m, 3H), 7.0-6.93 (m, 1H), 3.29 (br. s, 4H); MS (ESI+) for C20 H19 F2 N3O2 S m/z 403.94 (M+H)⁺.

Example 89 4-piperazin-1-yl-naphthalene-1-sulfonic acid(2-trifluoromethoxy-phenyl)-amide, hydrochloride

N-(2-tri-Fluoromethoxyphenyl)-4-fluoronephthylsulphonamide—Method E;Yield (43%); ¹H NMR (DMSO-d₆) δ 10.58 (s, 1H), 8.80-8.76 (m, 1H),8.20-8.17 (m, 1H), 8.08 (dd, J=8.3, 5.4 Hz, 1H), 7.84-7.74 (m, 2H), 7.42(dd, J=10.2, 8.3 Hz, 1H), 7.32-7.18 (m, 4H).

The final product was prepared according to Method F; Yield (48%); ¹HNMR (DMSO-d6) δ 10.49 (s, 1H), 9.27 (br. s, 2H), 8.75-8.72 (m, 1H),8.24-8.21 (m, 1H), 8.02 (d, J=7.9 Hz, 1H), 7.71-7.62 (m, 2H), 7.32-7.17(m, 5H), 3.38 (br. s, 4H), 3.28 (br. s, 4H); S (ESI+) for C21 H20 F3 N3O3 S m/z 451.9 (M+H)⁺.

Example 90 4-piperazin-1-yl-naphthalene-1-sulfonic acid(3-phenoxy-phenyl)-amide, hydrochloride

N-(3-phenyloxyphenyl)-4-fluoronephthylsulphonamide—Method E; Yield 0.64g (100%); ¹H NMR (DMSO-d₆) δ 10.80 (br. s, 1H), 8.71-8.68 (m, 1H),8.19-8.16 (m, 1H), 8.10 (dd, J=8.3, 5.4 Hz, 1H), 7.85-7.74 (m, 2H), 7.45(dd, J=10.2, 8.3 Hz, 1H), 7.38-7.31 (m, 2′ H), 7.18-7.10 (m, 2H),6.82-6.73 (m, 3H), 6.58-6.55 (m, 2H); MS (ESI−) for C22 H16 F N O3 S m/z392.2 (M−H)⁻.

The final product was prepared according to Method F; Yield 0.08 g(31%); ¹H NMR (DMSO-d6) δ 10.76 (s, 1H), 9.37 (br. s, 2H), 8.67-8.63 (m,1H), 8.23-8.20 (m, 1H), 8.02 (d, J=8.2 Hz, 1H), 7.73-7.62 (m, 2H),7.41-7.35 (m, 2H), 7.20-7.09 (m, 3H), 6.84-6.73 (m, 3H), 6.60-6.52 (m,2H), 3.47-3.37 (m, 8H); MS (ESI+) for C26 H25 N3 O3 S m/z 459.95 (M+H)⁺.

Example 91 4-piperazin-1-yl-naphthalene-1-sulfonic acid(3-trifluoromethoxy-phenyl)-amide, hydrochloride

N-(3-Trifluoromethoxyphenyl)-4-fluoronaphthalensulphonamide—Method E;Yield (35%); ¹H NMR (DMSO-d6) δ 11.01 (br.s, 1H), 8.74-8.71 (m, 1H),8.26 (dd, J=8.3, 5.3 Hz, 1H), 8.16 (d, J=9.0 Hz, 1H), 7.86-7.82 (m, 1H),7.78-7.74 (m, 1H), 7.46 (dd, J=10.0, 8.5 Hz, 1H), 7.27 (t, J=8.3 Hz,1H), 7.02-6.90 (m, 3H); MS (ESI−) for C17 H11 F4 N O3 S m/z 383.8(M−H)⁻.

The final product was prepared according to Method F; Yield (35%); ¹HNMR (DMSO-d6) δ 11.07 (s, 1H), 9.63 (br. s, 1H), 9.31 (br. s, 1H), 8.66(d, J=8.4 Hz, 1H), 8.21-8.18 (m, 2H), 7.75-7.62 (mil, 2H), 7.29-7.21 (m,2H), 7.03-6.86 (m, 3H), 3.32-3.28 (m, 8H); MS (ESI+) for C26 H25 N3 O3 Sm/z 451.94 (M+H)⁺.

Example 92 4-piperazin-1-yl-naphthalene-1-sulfonic acid(2-chloro-5-methyl-phenyl)-amide, hydrochloride

The final product was prepared according to method F: ¹H NMR ((DMSO-d6)δ; 10.10 (brs, 1H), 9.25 (brs, 2H), 8.76-8.66 (m, 1H), 8.27-8.17 (m,1H), 8.00-7.94 (m, 1H), 7.71-7.60 (m, 2H), 7.25-7.11 (m, 2H), 7.02 (s,1H), 6.99-6.92 (m, 1H), 3.40-3.20 (m, obscured by solvent signal) 2.17(s, 3H), MS (posESI) m/z=416 (M+H).

Example 93 4-piperazin-1-yl-naphthalene-1-sulfonic acid(4-isopropyl-phenyl)-amide, hydrochloride

The final product was prepared according to method F: ¹H NMR ((DMSO-d6)δ; 10.52 (s, 1H), 9.26 (brs, 2H), 8.74-8.66 (m, 1H), 8.27-8.11 (m, 2H),7.76-7.60 (m, 2H), 7.26.7.17 (m, 1H), 7.06-6.89 (m, 4H), 3.40-3.20 (m,obscured by solvent signal), 2.77-2.61 (m, 1H), 1.05 (d, J=6.87 Hz, 6H),MS (posESI) m/z=410 (M+H).

Example 94N-(3,5-Difluorophenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide,hydrochloride

The final product was prepared according to Method F using the crudeN-(3,5-difluorophenyl)-4-fluoronaphthalene-1-sulfonamide (50 mg, 0.15mmol) afforded the title compound (20 mg, 31%) as a yellow solid. ¹H NMR(DMSO) δ 11.33 (s, 1H), 9.35 (br s, 2H), 8.69 (m, 1H), 8.30-8.18 (m,2H), 7.80-7.61 (m, 2H), 7.30-7.21 (m, 1H), 6.84-6.62 (m, 3H), 3.45-3.24(m, 8H); MS m/z (M+1) 404.

Example 951-[4-(3,4-Dihydroquinolin-1(2H)-ylsulfonyl)-1-naphthyl]piperazine,hydrochloride

4-Fluoronaphthalene-1-sulfonyl chloride—To a stirred solution of1-fluoronaphthalene (8.0 g, 55 mmol) in concentrated trifluoroaceticacid (40 ml), chlorosulfonic acid was added slowly (15 min) at 0° C. Themixture was stirred at room temperature for an additional 2 hours andthen added slowly onto a stirred ice slurry. The formed precipitatefiltered off, washed with cold water and dried in vacuo to give thetitle compound (7.3 g) as a white solid.

1-[(4-Fluoro-1-naphthyl)sulfonyl]-1,2,3,4-tetrahydroquinoline—Method E:To a stirred solution of 4-fluoronaphthalene-1-sulfonyl chloride (200mg, 0.82 mmol) in DCM (1 ml) was added 1,2,3,4-tetrahydroquinoline (123μl, 0.98 mmol) followed by pyridine (0.25 ml). The reaction mixture wasstirred over night, diluted with DCM and washed with 1M HCl (3×3 ml).Subsequent drying of the organic phase using MgSO₄, and removal of thesolvents in vacuo afforded the title compound (280 mg, 100%) as a whitesolid. ¹H NMR (CDCl₃) δ 8.24-8.10 (m, 3H), 7.68-7.62 (m, 1H), 7.58-7.51(m, 1H), 7.42-7.34 (m, 1H), 7.23-7.04 (m, 3H), 6.96-6.89 (m, 1H),3.84-3.74 (m, 2H), 2.39-2.28 (m, 2H), 1.63-1.49 (m, 1H); MS m/z (M+1)342.

The final product was prepared according to Method F: A stirred solutionof 1-[(4-fluoro-1-naphthyl)sulfonyl]-1,2,3,4-tetrahydroquinoline (50 mg,0.15 mmol) and piperazine (80 mg, 0.9 mmol) in DMSO (1 ml) was heated at95° C. over night. The reaction mixture was allowed to reach roomtemperature and was subsequently added dropwise into water. The formedsolid was isolated, re-dissolved in MeOH and treated with an excess of1M HCl in diethyl ether. Removal of the solvents in vacuo afforded thetitle compound (60 mg, 83%) as a white solid. ¹H NMR (DMSO) δ 9.17 (brs, 2H), 8.23-8.06 (m, 3H), 7.61-7.55 (m, 1H), 7.48-7.38 (m, 2H),7.29-7.23 (m, 1H), 7.19-7.12 (m, 1H), 7.09-6.98 (m, 2H), 3.78-3.71 (m,2H), 3.44-3.30 (m, 8H), 2.42-2.32 (m, 2H), 1.57-1.48 (m, 2H); MS m/z(M+1) 408.

Example 96 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid(3-nitro-phenyl)-amide, hydrochloride

The final product was prepared according to Method F: ¹H NMR ((DMSO-d6)δ; 8.68-8.63 (m, 1H), 8.27-8.13 (m, 2H), 7.78 (s, 1H), 7.72-7.53 (m,3H), 7.35-7.16 (m, 3H), 3.55-3.40 (m, 6H), 3.34-3.27 (m, obscured inpart by solvent signal), 2.22-2.13 (m, 2H), MS (posESI) m/z=427 (M+H).

Example 97 4-piperazin-1-yl-naphthalene-1-sulfonic acid(3-nitro-phenyl)-amide, hydrochloride

The final product was prepared according to Method F: ¹H NMR ((DMSO-d6)δ; 8.68-8.60 (m, 1H), 8.24-8.13 (m, 2H), 7.77 (s, 1H), 7.71-7.53 (m,3H), 7.30-7.20 (m, 2H), 7.16-7.10 (m, 1H), 3.45-3.40 (m, 4H), 3.31-3.20(m, 4H), MS (posESI) m/z=413 (M+H).

Example 98 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid(3-nitro-phenyl)-methyl-amide, hydrochloride

The final product was prepared according to Method F: ¹H NMR (DMSO-d6)δ; 8.21 (d, J=8.47 Hz, 1H), 8.12 (d, J=8.79 Hz, 1H), 8.01-7.95 (m, 2H),7.64 (s, 1H), 7.54-7.39 (m, 3H), 7.34-7.28 (m, 1H), 7.23-7.18 (m, 1H),3.60-3.30 (m, 8H), 3.17 (s, 3H), 2.24-2.16 (m, 2H), MS (posESI) m/z=441(M+H).

Example 99 N-(4-Methylphenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide,hydrochloride

4-Fluoro-N-(4-methylphenyl)naphthalene-1-sulfonamide—Method E: Use of4-methylaniline afforded the title compound (500 mg, 95%) as an oil bythe application of the general procedure A described above. ¹H NMR(CDCl₃) δ 8.82-8.75 (m, 1H), 8.22-8.13 (m, 2H), 7.73-7.58 (m, 2H), 7.44(s, 1H), 7.11-7.02 (m, 1H), 6.93-6.80 (m, 4H), 2.17 (s, 3H); MS m/z(M+1) 316.

The final product was prepared according to Method E: Use of4-fluoro-N-(4-methylphenyl)naphthalene-1-sulfonamide afforded the titlecompound (200 mg, 30%), after washing with methanol, as a yellow solid.¹H NMR (DMSO) δ 10.46 (s, 1H), 9.30 (br s, 2H), 8.76-8.65 (m, 1H),8.25-8.06 (m, 2H), 7.78-7.59 (m, 2H), 7.25-7.14 (m, 1H), 6.98-6.83 (4H),3.41-3.22 (m, 8H), 2.09 (s, 3H); MS m/z (M+1) 382.

Example 100N-(3-Chloro-4-methylphenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide,hydrochloride

The final product was prepared according to Method E: yield 100%, purity93% ¹H NMR (500 MHz, DMSO-D6) δ ppm 2.26 (s, 3H), 2.74 (m, 4H), 3.54 (m,4H), 7.23 (m, 4H), 7.83 (m, 2H), 8.31 (m, 2H), 8.81 (s, 1H), 9.11 (s,1H, N—H), 10.86 (s, 1H, N—H); MS (ESI+) for C21 H22 Cl N3 O2 S HCl m/z(M+H)⁺. 416.1; MS (ESI−) for C21 H22 Cl N3 O2 S HCl m/z (M−H)⁻. 414.1.

Example 101 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid(2,3-dimethyl-phenyl)-methyl-amide, hydrochloride

The final product was prepared according to Method F: ¹H NMR (DMSO-d6)δ; 8.51-8.41 (m, 1H), 8.39-8.30 (m, 1H), 8.11-7.99 (m, 1H), 7.68-7.56(m, 1H), 7.54-7.42 (m, 1H), 7.35-7.23 (m, 1H), 7.13-7.02 (M, 1H),6.90-6.78 (m, 1H), 6.62-6.47 (m, 1H), 3.70-3.40 (m, 8H), 3.17 (s, 3H),2.25 (s, 3H), 2.10 (s, 3H), MS (posESI) m/z=424 (M+H).

Example 102 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid(4-isopropyl-phenyl)-amide, hydrochloride

The final product was prepared according to Method F: ¹H NMR ((DMSO-d6)δ; 8.74 (d, J=8.16 Hz, 1H), 8.33 (d, J=8.48 Hz, 1H), 8.15-8.10 (m, 1H),7.72-7.62 (m, 2H), 7.25-7.21 (m, 1H), 6.99-6.86 (m, 4H), 3.62-3.57 (m,2H), 3.56-3.50 (m, 4H), 3.41-3.35 (m, 2H), 2.79-2.69 (m, 1H), 2.32-2.22(m, 2H), 1.14-1.10 (m, 6H), MS (posESI) m/z=424 (M+H).

Example 103 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid(4-isopropyl-phenyl)-methyl-amide, hydrochloride

The final product was prepared according to Method F: ¹H NMR (DMSO-d6)δ; 8.13-8.07 (m, 1H), 8.01-7.93 (m, 1H), 7.51-7.41 (m, 1H), 7.38-7.15(m, 2H), 7.00-6.95 (m, 2H), 6.89-6.85 (m, 2H), 3.59-3.28 (m, 8H), 3.09(s, 3H), 2.81-2.71 (m, 1H), 1.11 (d, J=6.60 Hz, 6H), MS (posESI) m/z=438(M+H).

Example 104 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid(2,4-dimethyl-phenyl)-amide, hydrochloride

The final product was prepared according to Method F: ¹H NMR ((DMSO-d6)δ; 8.70-8.61 (m, 1H), 8.30-8.20 (m, 1H), 7.91-7.78 (m, 1H), 7.60-7.51(m, 2H), 7.14-7.06 (m, 1H), 6.76-6.59 (m, 3H), 3.64-3.40 (m, 6H),3.35-3.30 (m, obscured in part by solvent signal), 2.24-2.13 (m, 2H),2.07 (s, 3H), 1.76 (s, 3H), MS (posESI) m/z=410 (M+H).

Example 105 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid(2-chloro-5-methyl-phenyl)-amide, hydrochloride

The final product was prepared according to Method F: ¹H NMR ((DMSO-d6)δ; 8.67-8.61 (m, 1H), 8.24-8.19 (m, 1H), 7.95 (d, J=8.16 Hz, 1H),7.57-7.56 (m, 2H), 7.21-7.18 (m, 1H), 7.12 (d, J=8.17 Hz, 1H), 6.89 (d,J=8.17 Hz, 1H), 6.78-6.75 (m, 1H), 3.52-3.47 8 m, 2H), 3.45-3.40 (m,4H), 3.31-3.26 (m, 2H), 2.20-2.10 (m, 2H), 2.14 (s, 3H), MS (posESI)m/z=430 (M+H).

Example 106 4-piperazin-1-yl-naphthalene-1-sulfonic acid(2,5-dimethoxy-phenyl)-amide, hydrochloride

The final product was prepared according to Method F: ¹H NMR ((DMSO-d6)δ; 8.80-8.72 (m, 1H), 8.27-8.19 (m, 1H), 7.98 (d, J=8.18 Hz, 1H),7.74-7.60 (m, 2H), 7.17 (d, J=7.91. Hz, 1H), 6.76-6.75 (m, 2H),6.62-6.55 (m, 1H), 3.60 (s, 3H), 3.40-3.20 (m, obscured by solventsignal), 3.12 (s, 3H), MS (posESI) m/z=428 (M+H).

Example 107 4-piperazin-1-yl-naphthalene-1-sulfonic acid(3-acetyl-phenyl)-amide; hydrochloride

The final product was prepared according to Method F: ¹H NMR ((DMSO-d6)δ; 8.79-8.72 (m, 1H), 8.29-8.21 (m, 2H), 7.75-7.62 (m, 2H), 7.59-7.52(m, 2H), 7.26-7.19 (m, 3H), 3.52-3.44 (m, 4H), 3.39-3.30 (m, obscured bysolvent signal), 2.43 (s, 3H), MS (posESI) m/z=410 (M+H).

Example 108 4-piperazin-1-yl-naphthalene-1-sulfonic acid(2,4-dimethyl-phenyl)-amide, hydrochloride

The final product was prepared according to Method F: ¹H NMR ((DMSO-d6)δ; 8.81-8.72 (m, 1H), 8.34-8.25 (m, 1H), 7.98 (d, J=8.18 hz, 1H),7.71-7.60 (m, 2H), 7.14 (d, J=8.18 Hz, 1H), 6.81 (s, 1H), 6.76-6.72 (m,2H), 3.58-3.47 (m, 4H), 3.44-3.30 (m, obscured in part by solventsignal), 2.16 (s, 3H), 1.84 (s, 3H), MS (posESI) m/z=396 (M+H).

Example 109 4-piperazin-1-yl-naphthalene-1-sulfonic acid(3-trifluoromethyl-phenyl)-amide, hydrochloride

The final product was prepared according to Method F: ¹H NMR ((DMSO-d6)δ; 8.72-8.64 (m, 1H9, 82.7-8.16 (m, 2H), 7.81-7.62 (m, 2H), 7.45-7.19(m, 5H), 3.40-3.20 (m, obscured by solvent signal), MS (posESI) m/z=436(M+H).

Example 110 4-piperazin-1-yl-naphthalene-1-sulfonic acidbiphenyl-2-ylamide, hydrochloride

The final product was prepared according to Method F: ¹H NMR ((DMSO-d6)δ; 9.71 (s, 1H), 944 (brs, 2H), 8.51-8.42 (m, 1H), 8.24-8.15 (m, 1H),7.83 (d, J=8.18 Hz, 1H), 7.66-7.49 (m, 2H), 7.29-6.98 (m, 10H),3.50-3.30 (m, obscured by solvent signal), MS (posESI) m/z=444 (M+H).

Example 111 4-piperazin-1-yl-naphthalene-1-sulfonic acid(3-benzyloxy-phenyl)-amide

N-(3-phenyloxyphenyl)-4-fluoronaphthalensulphonamide—Method E; Yield 9.2g (47%). ¹H NMR (DMSO-d₆) δ 10.75 (s, 1H), 8.75 (d, J=8.4 Hz, 1H),8.23-8.14 (m, 2H), 7.87-7.73 (m, 2H), 7.44 (dd, J=10.2, 8.3 Hz, 1H),7.34-7.29 (m, 5H), 7.03 (t, J=8.2 Hz, 1H), 6.66-6.56 (m, 3H), 4.93 (s,2H); MS (ESI+) for C23 H18 F N O3 S m/z 407 (M+H)⁺.

The final product was prepared according to Method F: Yield 0.6 g (78%);¹H NMR (DMSO-d₆) δ 10.67 (s, 1H), 9.30 (br. s, 2H), 8.69 (d, J=7.7 Hz,1H), 8.21 (d, J=8.4 Hz, 1H), 8.13 (d, J=8.2 Hz, 1H), 7.75-7.61 (m, 2H),7.35-7.30 (m, 5H), 7.19 (d, J=8.2 Hz, 1H), 7.03 (t, J=8.2 Hz, 1H),6.68-6.54 (m, 3H), 4.93 (s, 2H), 3.36-3.29 (m, 8H); MS (ESI+) for C27H27 N3 O3 S m/z 474 (M+H)⁺.

Example 112

N-(4-fluorophenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide,hydrochloride-4-Fluoro-N-(4-fluorophenyl)naphthalene-1-sulfonamide—MethodE: Use of 4-methoxyaniline afforded the title compound (475 mg, 86%) asan oil by the application of the general procedure A described above. ¹HNMR (CDCl₃) δ 8.79-8.71 (m, 1H), 8.23-8.10 (m, 2H), 7.75-7.59 (2H),7.52-7.45 (m, 1H), 7.15-7.04 (m, 1H), 6.96-6.73 (m, 4H); MS m/z (M+1)320.

The final product was prepared according to Method F: Use of4-fluoro-N-(4-fluorophenyl)naphthalene-1-sulfonamide afforded the titlecompound (95 mg, 15%), after recrystallization from methanol, as a whitesolid by the application of the general procedure B described above. ¹HNMR (DMSO) δ 10.60 (s, 1H), 9.37 (br s, 2H), 8.73-8.65 (m, 1H),8.25-8.17 (m, 1H), 8.13-8.06 (m, 1H), 7.76-7.60 (m, 2H), 7.22-7.15 (m,1H), 7.04-6.95 (m, 4H), 3.43-3.24 (m, 8H); MS m/z (M+1) 386.

Example 113N-(3-Ethylphenyl)-4-piperazin.1.ylnaphthalene-1-sulphonamine,hydrochloride

N-(3-Ethylphenyl)-4-fluoronaphthalene-1-sulfonamide—Method E: yield 80%,purity 92%. ¹H NMR (270 MHz, CDCl₃) δ ppm 1.03 (t, J=7.52 Hz, 3H), 2.45(q, J=7.65 Hz, 2H), 6.68-6.72 (m, 2H, N—H), 6.87 (d, J=7.13 Hz, 1H),6.99-7.13 (m, 2H), 7.65-7.72 (m, 2H), is 8.13-8.20 (m, 2H), 8.65 (d,J=8.44 Hz, 1H); MS (ESI+) for C18 H16 F N O2 S m/z 329.393 (M+H)⁺.330.0; MS (ESI−) for C18 H16 F N O2 S m/z 329.393 (M−H)⁻. 328.1

The final product was prepared according to Method F: yield 61%, purity98%. ¹H NMR (500 MHz, DMSO) δ 8.67-8.65 (m, 1H), 8.16-8.10 (m, 2H),7.66-7.57 (m, 2H), 7.14 (d, J=8.56 Hz, 1H), 6.97-6.94 (m, 1H), 6.78-6.76(m, 2H), 6-70-6.69 (m, 1H), 3.30-3.28 (m, 2H), 3.22-3.19 (m, 2H), 2.34(q, J=17 Hz, 2H), 1.94 (tr, J=17 Hz, 3H); MS (ESI+) for C22 H25 N3 O2 SHCl m/z 431.98 (M−HCl+H)⁺. 396.1; MS (ESI−) for C22 H25 N3 O2 S HCl m/z(M−HCl−H)⁻. 394.1

Example 1144-piperazinyl-N-[3-(trifluoromethyl)phenyl]naphthalene-1-sulfonamide,hydrochloride

The final product was prepared according to Method F: Use of4-fluoro-N-(3-trifluoromethythiophenyl)naphthalene-1-sulfonamideafforded the title compound (0.08 g), gave 0.060 g of the desiredproduct, yield 85%, purity 96%.

¹H NMR (270 MHz, CD₃OD) δ 8.74-8.71 (m, 1H), 8.26-8.19 (m, 2H),7.75-7.65 (m, 2H), 7.32 (br.s, 1H), 7.23-7.14 (m, 4H), 3.57-3.47 (m,4H), 3.35-3.30 (m, 4H); MS (ESI+) for C21 H20 F3 N3 O2 S2 HCl m/z467.09+35.46 (M+H)⁺ 468.0; MS (ESI+) for C21 H20 F3 N3 O2 S2 HCl m/z467.09+35.46 (M−H)⁻ 466.1.

Example 115 4-piperazinyl-N-[3-benzoylphenyl]naphthalene-1-sulfonamide,hydrochloride

The final product was prepared according to Method F: yield 25%, purity97%. ¹H NMR (270 MHz, CD₃OD) δ 8.76-8.72 (m, 1H), 8.29-8.26 (m, 1H),8.17 (d, J=8, 1 Hz, 1H), 7.73-7.60 (m, 3H), 7.55-7.44 (m, 4H), 7.34-7.28(m, 4H), 7.18 (d, J=8, 1 Hz, 1H), 3.54-3.50 (m, 4H), 3.37-3.30 (m, 4H);MS (ESI+) for C27 H25 N3 O3 S HCl m/z 471.17+35.46 (M+H)⁺ 472.1; MS(ESI+)+) for C27 H25 N3 O3 S HCl m/z 471.17+35.46 (M−H)⁻ 470.01.

Example 1164-piperazinyl-N-[3-(4-bromo-1-methyl-1H-pyrazol-3-yl)phenyl]naphthalene-1-sulfonamide,hydrochloride

The final product was prepared according to Method F: yield 81%, purity96%. ¹H NMR (270 MHz, CD₃OD) δ 8.78-8.74 (m, 1H), 8.27-8.24 (m, 1H),8.19 (d, J=8, 1 Hz, 1H), 7.75-7.64 (m, 2H), 7.46 (s, 1H), 7.31-7.25 (m1H), 7.19-7.16 (m, 2H), 7.02-6.96 (m, 2H), 3.57-3.49 (m, 4H), 3.52 (s,3H), 3.35-3.30 (m, 4H); MS (ESI+) for C24 H24 Br N5 O2 S HCl m/z525.08+35.46 (M+H)⁺ 526.0; MS (ESI+) C24 H24 Br N5 O2 S HCl m/z 525.08+35.46 (M−H)⁻ 524.1.

Example 117 4-piperazinyl-N-[3-biphenylphenyl]naphthalene-1-sulfonamide,hydrochloride

The final product was prepared according to Method F: yield 33%, purity95%. ¹H NMR (270 MHz, CD₃OD) δ 8.83-8.80 (m, 1H), 8.26-8.22 (m, 2H),7.79-7.68 (m, 2H), 7.39-7.35 (m, 5H), 7.23-7.19 (m, 4H), 7.03-6.99 (m,1H), 3.52-3.47 (m, 4H), 3.35-3.30 (m, 4H); MS (ESI+) for C26 H25 N3 O2 SHCl m/z 443.17+36.45 (M+H)⁺ 444.1; MS (ESI−) for C26 H25 N3 O2 S HCl m/z443.17+36.45 (M−H)⁻ 442.2.

Synthesis of Examples and Intermediates in Table IV

General Method H

Example 118N-[1-(4-Methyl-1-piperazinyl)-3-isoquinolinyl]benzenesulfonamide,hydrochloride

To a solution of 1-(4-methyl-1-piperazinyl)-3-isoquinolinylamine(commercially available; 0.26 g, 1.07 mmol) and pyridine (0.60 mL, 7.51mmol) in CH₂Cl₂ (3.0 mL) was added benzenesulfonyl chloride (151 μL,1.18 mmol) in CH₂Cl₂ (1 mL). The mixture was stirred at room temperaturefor 16 hours and left in the refrigerator for 24 hours. The precipitatewas collected by filtration to give 0.255 g (57%) of the pure product asthe HCl-salt: ¹H NMR (DMSO-d6) δ 10.93 (s, 2H), 7.96-7.90 (m, 3H),7.79-7.75 (m, 1H), 7.64-7.56 (m, 4H), 7.44-7.38 (m, 1H), 7.01 (s, 1H9,3.70-3.15 (m, partly obscured by solvent signal, 8H), 2.79 (s, 3H); MS(posEI-DIP) m/z 382 (M⁺).

Example 1192,4-di-Fluoro-N-[1-(4-methyl-1-piperazinyl)-3-isoquinolinyl]benzenesulfonamide,hydrochloride

The title compound was prepared from1-(4-methyl-1-piperazinyl)-3-isoquinolinylamine (commercially available;0.209 g, 0.862 mmol) using the method described in the example thatfollows: yield 0.152 g (65%); ¹H NMR (DMSO-d6) δ; 11.35 (s, 1H), 11.09(br s, 1H), 8.15-8.04 (m, 1H), 7.97-7.90 (m, 1H), 7.83-7.35 (m, 5H),6.95 (s, 1H), 3.70-3.10 (m, 8H), 2.85-2.75 (m, 3H); MS (posESI) m/z 419(M+H).

Example 1204-Bromo-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 11.07 (s, 1H), 10.75 (br s, 1H), 7.98-7.75 (m, 5H),7.66-7.58 (m, 1H), 7.52 (s, 1H), 7.47-7.37 (m, 1H), 7.00 (brs, 1H),3.70-3.20 (obscured in part by solvent signal, 8H), 2.85-2.80 (m, 2H),MS (posESI) m/z=461 (M+H)

Example 121 5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonic acid[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-amide, hydrochloride

¹H NMR (DMSO-d6) δ; 11.47 (br s, 1H), 10.55 (br s, 1H), 8.14-8.07 (m,1H), 8.01-7.98 (m, 1H), 7.96-7.98 (m, 1H), 7.82-7.76 (m, 1H), 7.67-7.52(m, 2H), 7.47-7.39 (m, 1H), 7.06 (s, 1H), 3.80-3.65 (m, 2H), 3.60-3.25(m, obscured by solvent signal), 2.80-2.73 (m, 3H)), MS (posESI) m/z=487(M+H)

Example 1223-Chloro-2-methyl-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 11.24 (br s, 1H), 10.56 (br s, 1H), 8.10-8.05 (m,1H), 7.95-7.89 (m, 1H), 7.80-7.69 (m, 2H), 7.66-7.57 (m, 1H), 7.53-7.35(m, 2H), 6.94 (s, 1H), 3.70-330 (m, obscured by solvent signal),3.29-3.10 (m, 4H), 3.85-2.79 (m, 3H),), MS (posESI) m/z=431 (M+H).

Example 1233,4-Dichloro-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 11.17 (s, 1H), 10.50 (br s, 1H), 8.16-8.14 (m, 1H),7.98-7.93 (m, 1H), 7.91-7.89 (m, 2H), 7.85-7.80 (m, 1H), 7.68-7.60 (m,1H), 7.49-7.41 (m, 1H), 7.04 (s, 1H), 3.85-3.20 (m, obscured by solventsignal), 2.87-2.83 (m, 3H),), MS (posESI) m/z=451 (M+H).

Example 1244-Methyl-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 10.88 (m, brs, 1H), 7.95-7.88 (m, 1H), 7.85-7.74 (m,3H), 7.65-7.56 (m, 1H), 7.51-7.34 (m, 4H), 7.14-7.09 (m, 1H), 6.99 (s,1H), 3.75-3.45 (m, obscured by solvent signal, 4H), 3.35-3.15 (m, 4H),2.84 (d, J=4.75 Hz, 3H), 2.33 (s, 3H)), MS posESI) m/z=397(M+H).

Example 1253-Methoxy-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 10.93 (brs, 1H), 10.69 (brs, 1H), 7.93 (d, J=8.19Hz, 1H), 7.79 (d, J=7.92 Hz, 1H), 7.65-7.57 (m, 1H), 7.52-7.37 (m, 4H),7.24-7.13 (m, 1H), 7.03 (s, 1H), 3.78 (s, 3H), 3.75-3.20 (m, obscured bysolvent signal, 8H), 2.81 (d, J=4.48 Hz, 3H), MS (posESI) m/z=413(M+H).

Example 126 5-Chloro-thiophene-2-sulfonic acid[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-amide, hydrochloride

¹H NMR (DMSO-d6) δ; 7.76-7.21 (m, 1H), 7.01-6.96 (m, 1H), 6.89-6.82 (m,1H), 6.74-6.71 (m, 1H), 6.70-6.66 (m, 1H), 6.40 (brs, 1H), 6.22 (d,J=3.96 Hz, 1H), 3.20-3.10 (m, 2H), 2.87-2.75 (m, 2H), 2.70-2.50 (m,obscured in part by solvent signal, 4H), 2.19 (brs, 3H), MS (posESI)m/z=423(M+H).

Example 127N-{2-Chloro-4-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-ylsulfamoyl]-phenyl}-acetamide,hydrochloride

¹H NMR (DMSO-d6) δ; 10.03 (s, 1H), 10.52 (brs, 1H), 7.93 (d, J=8.44 Hz,1H), 7.78 (d, J=7.92 Hz, 1H), 7.71 (d, J=2.11 Hz, 1H), 7.65-7.57 (m,1H), 7.57-7.51 (dd, J=2.11 and 8.44 Hz, 1H), 7.45-7.37 (m, 1H), 6.99 (s,1H), 6.80 (d, 8.44 Hz, 1H), m3.82-3.71 (m, 2H), 3.60-3.20 (m, obscuredby solvent signal) 2.84 (d, J=4.49 hz, 3H), MS (posESI) m/z=474(M+H).

Example 128 2,5-Dichloro-thiophene-3-sulfonic acid[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-amide, hydrochloride

¹H NMR (DMSO-d6) δ; 794-7.89 (m, 1H), 7.77-7.72 (m, 1H), 7.63-7.56 (m,1H), 7.46 (s, 1H), 7.44-7.36 (m, 1H), 3.50-3.20 (m, obscured by solventsignal), 2.70-2.50 m, obscured by solvent signal), 2.32 (brs, 3H), MS(posESI) m/z=457(M+H).

Example 129N-[1-(4-Methyl-piperazin-1-yl)-isoquinolin-3-yl]-3-trifluoromethyl-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 11.17 (s, 1H), 10.71 (brs, 1H), 8.27-8.17 (m, 2H),8.07-8.01 (m, 1H), 7.97-7.79 (m, 3H), 7.67-7.60 (m, 1H), 7.48-7.40 (m,1H), 7.06 (s, 1H), 3.70-3.40 (m, m, obscured by solvent signal),3.31-3.14 (m, 4H), 2.82 (d, J=4.75 Hz, 3H), MS (posESI) m/z=451(M+H).

Example 130N-[1-(4-Methyl-piperazin-1-yl)-isoquinolin-3-yl]-4-phenoxy-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 10.91 (s, 1H), 10.79 brs, 1H), 7.98-7.89 (m, 3H),7.81-7.74 (m, 1H), 7.66-7.55 (m, 1H), 7.49-7.37 (m, 3H), 7.28-7.20 (m,1H), 7.13-7.06 (m, 4H), 7.00 (s, 1H), 3.77-3.66 (m, 2H), 3.50-3.20 (m,6H), 2.82 (d, J=4.49 Hz, 3H), MS (posESI m/z=475 (M+H).

Example 1315-Bromo-2-methoxy-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 10.90 (s, 1H), 10.75 (brs, 1H), 7.99 (d, J=2.64 Hz,1H), 7.91 (m, d, J=8.45 Hz, 1H), 7.80-7.73 (m, 2H), 7.65-7.57 (m, 1H),7.45-7.37 (m, 1H), 7.14 (d, J=8.47 Hz, 1H), 3.82 (s, 3H), 3.68-3.55 (m,2H), 3.52-3.38 (m, 2H), 3.35-3.20 (m, 4H), 2.84 (d, J=4.49 Hz, 3H), MS(posESI m/z=491(M+H).

Example 1322-Methanesulphonyl-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonamide,hydrochloride

MS (posESI) m/z=461 (M+H).

Example 133 3,5-Dimethyl-isoxazole-4-sulfonic acid[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-amide, hydrochloride

¹H NMR (DMSO-d6) δ; 11.17 (s, 1H), 10.54 (s, 1H), 7.99 (d, J=8.45 Hz,1H), 7.86 (d, J=7.92 Hz, 1H), 7.71-7.63 (m, 1H), 7.53-7.45 (m, 1H), 7.07(s, 3H), 3.75-3.64 (m, 2H), 3.55-3.45 (m, 2H), 3.35-3.15 (m, 4H), 2.84(d, J=4.49 Hz, 3H), 2.76 (s, 3H), 2.31 (s, 3H), MS (posESI) m/z=402(M+H).

Example 1342,4,6-Trimethyl-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonamide

¹H NMR (DMSO-d6) δ; 10.82 (s, 1H), 10.52 (brs, 1H), 7.92-7.87 (m, 1H),7.76-7.70 (m, 1H), 7.64-7.56 (m, 1H), 7.43-7.36 (m, 1H), 7.00 (s, 2H),6.88 (s, 1H), 6.74 (brs, 1H), 3.60-3.10 (m, 8H), 2.81 (d, J=4.75 Hz,3H), 2.61 (s, 6H), 2.22 (s, 3H), MS (posESI) m/z=425 (M+H).

Example 1353,4-Dimethoxy-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonamide,hydrochloride

¹H NMR (DMSO-d6) δ; 10.75 (brs, 1H), 10.72 (s, 1H), 7.95-7.90 (m, 1H),7.82-7.76 (m, 1H), 7.65-7.57 (m, 1H), 7.55-7.37 (m, 2H), 7.11 (d, J=8.71Hz, 1H)m 7.05 (s, 1H), 3.78 (s, 3H), 3.76 (s, 3H), 3.76-3.69 (m,obscured in part by —OMe), 3.51-3.19 (m, 6H), 2.82 (d, J=4.49 Hz, 3H),MS (posESI) m/z=443 (M+H).

Synthesis of Examples in Table V Example 136N-[8-(4-Methyl-1-piperazinyl)-5-quinolinyl]benzenesulfonamide,hydrochloride

To a solution of 8-(4-methyl-1-piperazinyl)-5-nitroquinoline (0.379 g,1.39 mmol) in THF:EtOH 1:4 solvent system was added Raney-Ni (1.0 mLsuspension in EtOH) followed by hydrazine hydrate (0.348 g, 6.95 mmol).The mixture was stirred vigorously at room temperature for 16 hours andthen filtered through celite pretreated with water. The filtrate wasconcentrated, and the residue was purified by column chromatography(SiO₂, CHCl₃/MeOH/NH₃ 9:1:0.4%) to give 0.337 g of8-(4-methyl-1-piperazinyl)-5-quinolinylamine. The amine was dissolved inCH₂Cl₂ (6.0 mL) and pyridine (0.785 mL, 9.73 mmol) and benzenesulfonylchloride (0.178 mL, 1.39 mmol) was added. The reaction mixture wasstirred at room temperature for 16 hours and then washed with saturatedaqueous NaHCO₃. The organic phase was dried with Na₂SO₄, filtered andconcentrated. The crude product was purified by column chromatography(SiO₂, CHCl₃/MeOH/NH₃ 9:1:0.4%) to give 0.130 g of the free base whichwas converted to its HCl-salt: ¹H NMR (DMSO-d6) δ; 11.09 (br s, 1H),10.32 (s, 1H), 8.94-8.89 (m, 1H), 8.55-8.48 (m, 1H), 7.68-7.65 (m, 2H),7.64-7.57 (m, 2H), 7.54-7.49 (m, 2H), 7.27-7.22 (m, 1H), 7.12-7.08 (m,1H), 3.95-3.84 (m, 2H), 3.55-3.49 (m, 2H), 3.45-3.35 (m, 2H), 3.26-3.16(m, 2H), 2.85-2.82 (m, 3); MS (posESI) m/z 383 (M+H).

Synthesis of Examples and Intermediates in Table VI

a) H₂O₂, CH₃COOH, 100° C.; b) Me₃SiCN, Toluene, (Me)₂N—CO—Cl, 65° C.; c)HBr/CH₃COOH, rt; d) Boc-piperazine, K₂CO₃, 90° C.; R—SO₂Cl, py, rt.Intermediate 20

3-Cyanomethylpyridine-N-oxide—Hydrogenperoxide (17 ml, 30% ww) was addedto a mixture of 3-cyanomethylpyridine (11 g, 93 mmol) and glacial aceticacid (55 ml) and heated at 100° C. overnight. The mixture was dilutedwith water (70 ml) and MnO₂ (5.0 g) was carefully added and stirred for5 hours (check peroxide content with peroxide sticks), and only smallamounts of peroxide was left. The mixture was concentrated in vacuo to40 ml and diluted with methanol (40 ml), filtered through a short plugof silica, and washed with methanol (400 ml). The filtrate wereconcentrated and recrystallized from chloroform and hexane to give thetitle compound (9.5 g, 76%). ¹H NMR (CDCl₃) δ 8.16 (s, 2H), 7.32 (s,2H), 3.73 (s, 2H); MS m/z (M+1) 135.

Intermediate 21

3-(Cyanomethyl)pyridine-2-carbonitrile—Trimethylsilylcyanide (4.2 ml, 32mmol) was added to a suspension of 3-cyanomethylpyridine-N-oxide (3.5 g,26 mmol) in toluene (35 ml) and after 1 minute dimethylcarbamylchloride(2.4 ml, 26 mmol) was added and the reaction was stirred overnight at65° C. EtOAc and 1N NaOH was added and the mixture was washed with water(2×). The organic phase was dried (MgSO₄) and evaporated. The crudeproduct was dissolved in ethanol (150 ml) and stirred overnight,filtered (remove byproduct) and concentrated (25 ml). After 30 min at 0°C. the yellow powder was filtered and washed with cold ethanol (1×) togive, after drying, the title compound (2.15 g, 57%). ¹H NMR (CDCl₃) δ8.71 (m, 1H), 8.03 (d, J=8.03 Hz, 1H), 7.62 (dd, J=8.16, 4.64 Hz, 1H),4.04 (s, 2H); MS m/z (M−1) 142.

Intermediate 22

6-Amino-8-bromo-1,7-naphthyridine—3-(Cyanomethyl)pyridine-2-carbonitrile(4.0 g, 28 mmol) was added carefully to HBr in acetic acid (33%) (25 ml)at rt. The red suspension was stirred for 1.5 h and filtered. The redsolid was washed with EtOAc (3×) and suspended in water. 1N NaOH wasadded dropwise until pH-8, and the suspension was stirred for 45 minutesand filtered. The red solid was washed with water (2×) and dried. Thecrude product was suspended in 5% MeOH in CH₂Cl₂ and filtered through ashort plug of silica, washing with 5% MeOH in CH₂Cl₂. Subsequentconcentration in vacuo afforded the title compound (3.85 g, 61%). ¹H NMR(DMSO) δ 8.58 (dd, J=4.02, 1.51 Hz, 1H), 8.01 (dd, J=8.53, 1.51 Hz, 1H),7.47 (dd, J=8.53, 4.02 Hz, 1H), 6.58 (s, 1H), 6.48 (s, 2H); MS m/z (M+1)226.

Intermediate 23

tert-Butyl 4-(6-amino-1,7-naphthyridin-8-yl)piperazine-1-carboxylate—Amixture of 6-amino-8-bromo-1,7-naphthyridine (650 mg, 2.9 mmol),BOC-piperazine (1.1 g, 5.9 mmol), potassium carbonate (2 g, 15 mmol) inDMSO (1 ml) was stirred at 90° C. for 3 days. Chloroform was added, themixture was filtered and the filtrate was washed with brine (3×100 ml).The organic phase was dried using potassium carbonate, filtered andconcentrated in vacuo to give a yellow oil. The oil was triturated withdiethyl ether and then eluted through a short silica plug usingchloroform. Subsequent concentration of the residue in vacuo gave thetitle compound (700 mg, 74%) as a yellow oil. ¹H NMR (CDCl₃) δ 8.43 (dd,J=4.09, 1.72 Hz, 1H), 7.67 (dd, J=8.31, 1.72 Hz, 1H), 7.25-7.20 (m, 1H),6.08 (s, 1H), 4.29 (s, 2H), 3.95-3.88 (m, 4H), 3.65-3-57 (m, 4H), 1.46(s, 9H); MS m/z (M+1) 330.

General Procedure I

To a stirred solution of tert-butyl4-(6-amino-1,7-naphthyridin-8-yl)piperazine-1-carboxylate (63 mg, 0.19mmol) in anhydrous dichloromethane (0.5 ml) and pyridine (0.25 ml) wasadded p-toluenesulfonyl chloride (36 mg, 0.19 mmol). The reactionmixture was stirred at room temperature over night and then concentratedin vacuo. The residue was purified using reversed-phase preparative HPLCto give the corresponding tert-butoxycarbonyl protected piperazineintermediate. This was dissolved in dichloromethane (1.5 ml) and treatedwith concentrated TFA (1 ml) at room temperature for 1.5 hours.

Example 1374-Methyl-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)benzenesulfonamide,trifluoroacetic acid

The title compound was prepared following the general procedure I (61mg, 65%) as a yellow solid. ¹H NMR (CD₃OD) δ 8.57-8.65 (m, 1H),8.06-7.98 (m, 1H), 7.86-7.78 (m, 2H), 7.53-7.43 (m, 1H), 7.36-7.26 (m,2H), 6.88 (s, 1H), 4.18-4.06 (m, 4H), 3.35-3.24 (m, 4H), 2.35 (s, 3H);MS m/z (M+1) 384.

Example 1384-Bromo-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)benzenesulfonamide,trifluoroacetic acid

The title compound was prepared following the general procedure I (14mg, 13%). ¹H NMR (CD₃OD) δ 8.70-8.63 (m, 1H), 8.14-8.05 (m, 1H),7.91-7.83 (m, 2H), 7.76-7.67 (m, 2H), 7.57-7.49 (m, 1H), 6.91 (s, 1H),4.19-4.09 (m, 4H), 3.38-3.28 (m, 4H); MS m/z (M+1) 449.

Example 139N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)naphthalene-1-sulfonamide,trifluoroacetic acid

The title compound was prepared following the general procedure I (66mg, 65%). ¹H NMR (CD₃OD) δ 8.82-8.76 (m, 1H), 8.58-8.54 (m, 1H),8.42-8.37 (m, 1H), 8.13-8.07 (m, 1H), 8.01-7.92 (m, 2H), 7.71-7.54 (m,3H), 7.47-7.40 (m, 1H), 6.80 (s, 1H), 4.02-3.96 (m, 4H), 3.24-3.18 (m,4H); MS m/z (M+1) 420.

Example 140N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)butane-1-sulfonamide,trifluoroacetic acid

The title compound was prepared following the general procedure I (48mg, 55%). ¹H NMR-(CD₃OD) δ 8.71-8.66 (m, 1H), 8.13-8.06 (m, 1H),7.58-7.51 (m, 1H), 6.83 (s, 1H), 4.33-4.23 (m, 4H), 3.51-3.38 (m, 6H),1.91-1.72 (m, 2H), 1.53-1.38 (m, 2H), 0.98-0.86 (m, 3H); MS m/z (M+2)351.

Example 1413-Trifluoromethyl-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)benzenesulfonamide,trifluoroacetic acid

The title compound was prepared following the general procedure I (60mg, 57%). ¹H NMR (CD₃OD) δ 8.70-8.63 (m, 1H), 8.28-8.17 (m, 2H),8.13-8.05 (m, 1H), 7.96-7.87 (m, 1H), 7.80-7.69 (m, 1H), 7.58-7.48 (m,1H), 6.93 (s, 1H), 4.18-4.07 (m, 4H), 3.39-3.27 (m, 4H); MS m/z (M+1)438.

Example 1423,4-Dimethoxy-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)benzenesulfonamide,trifluoroacetic acid

The title compound was prepared following the general procedure 1 (65mg, 63%). ¹H NMR (CD₃OD) δ 8.68-8.59 (m, 1H), 8.11-8.01 (m, 1H),7.61-7.40 (m, 3H), 7.04-6.92 (m, 2H), 4.22-4.10 (m, 4H), 3.81 (s, 3H),3.78 (s, 3H), 3.39-3.27 (m, 4H); MS m/z (M+1) 430.

Example 1432,4-Dichloro-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)benzenesulfonamide,trifluoroacetic acid

The title compound was prepared following the general procedure I (56mg, 53%). ¹H NMR (CD₃OD) δ 8.66-8.61 (m, 1H), 8.25-8.20 (m, 1H),8.06-8.00 (m, 1H), 7.65-7.61 (m, 1H), 7.57-7.47 (m, 2H), 6.76 (s, 1H),4.13-4.06 (m, 4H), 3.36-3.28 (m, 4H); MS m/z (M+2) 439.

Example 144N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)thiophene-2-sulfonamide,trifluoroacetic acid

The title compound was prepared following the general procedure I (57mg, 61%). ¹H NMR (CD₃OD) δ 8.71-8.64 (m, 1H), 8.14-8.05 (m, 1H),7.76-7.67 (m, 2H), 7.58-7.49 (m, 1H), 7.11-7.03 (m, 1H), 6.98 (s, 1H),4.27-4.15 (m, 4H), 3.40-3.28 (m, 4H); MS m/z (M+1) 376.

Example 1451-Phenyl-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)methanesulfonamide,trifluoroacetic acid

The title compound was prepared following the general procedure I (35mg, 37%). ¹H NMR (DMSO) δ 8.83 (br s, 1H), 8.52-8.40 (m, 2H), 7.47-7.41(m, 1H), 7.29-7.10 (m, 6H), 6.87 (s, 1H), 4.52 (s, 2H), 4.39-4.31 (m,4H), 3.30-3.22 (m, 4H); MS m/z (M+1) 384.

Synthesis of Examples and Intermediates in Table

Scheme 4 a) TMS-acethylene, Cu2O, Py, 80° C.; b) tBuO—Na, Pd2(dba)3,Xantphos, xilene, 120° C.; c) Raney-Ni, Hydrazine, THF/Ethanol; d)R—SO2-Cl, Py; e) HCl-diethyl ether.Intermediate 24

7-Iodo-5-nitro-1-benzofuran—A mixture of 4-nitro-2,5-diiodophenol (7.68g, 6.86 mmol), TMS-acetylene (0.67 g, 6.86 mmol) and Cu₂O (0.59 g, 4.12mmol) in pyridine (120 mL) was heated to 80 C for 48 h. The mixture wasfiltered through celite and the solvent was removed. Columnchromatography DCM/heptane 1:1 gave 0.35 g (18%) of product.

¹H NMR (CD₃OD) δ 8.60 (d, 1H, j=2.1 Hz), 8.51 (d, 1H, J=2.1 Hz), 7.84(d, 1H, J=2.1 Hz), 7.04 (d, 1H, J=2.4 Hz); MS (ESI) 289.8 (M+H)⁺; Purity(HPLC, column X) 93%.

Intermediate 25

1-Methyl-4-(5-Nitro-1-benzofuran-7-yl)-piperazine—A mixture of7-iodo-5-nitro-1-benzofuran (94.5 mg, 0.327 mmol), Xanthpos (19 mg.0.032 mmol), Pd₂(dba)₃ (7.4 mg, 0.025 mmol) and NaOt-Bu (44.0 mg, 0.458mmol), methylpiperazine (39.3 mg, 0.392 mmol) in xylene (3 mL) washeated to 120° C. overnight. The mixture was diluted with DCM andfiltered through silica. The product was eluted with DCM/MeOH×0.4% NH₃.Flash chromatography (DCM/MeOH×0.4% NH₃) gave 60 mg (70%) of BVT: ¹H NMR(CD₃OD) δ 8.07 (d, 1H, J=2.1 Hz), 7.70 (d, 1H, J=2.1 Hz), 7.58 (d, 1H,J=2.1 Hz), 6.84 (d, 1H, J=2.1 Hz), 3.44-3.40 (m, 4H), 2.65-2.62 (m, 4H),2.36 (s, 3H); MS (ESI) 262.0 (M+H)⁺; Purity (HPLC, column X) 95%.

Intermediate 26

tert-Butyl 4-(5-nitro-1-benzofuran-7-yl)-piperazine-1-carboxylate—Thetitle compound was prepared according to the same procedure used forIntermediate 25 using N-tert-butyl-piperazine carboxylate to afford 240mg (64%) of a white solid: ¹H NMR (CD₃OD) δ 8.08 (d, 1H, J=2.1 Hz), 7.72(d, 1H, J=2.1 Hz), 7.58 (d, 1H, J=2.1 Hz), 6.86 (d, 1H, J=2.1 Hz),3.66-3.62 (m, 4H), 3.34-3.31 (m, 4H), 1.46 (s, 9H); MS (ESI) 370.0(M+Na)⁺; Purity (HPLC, column X) 96%.

Intermediate 27

1-Methyl-4-(5-amino-1-benzofuran-7-yl)-piperazine

Intermediate 28

tert-Butyl4-(5-amino-1-benzofuran-7-yl)-piperazine-1-carboxylate—1-Methyl-4-(5-Nitro-1-benzofuran-7-yl)-piperazine(1 eq) and tert-butyl4-(5-nitro-1-benzofuran-7-yl)-piperazine-1-carboxylate (1 eq) werereduced to aromatic amine with Raney-Ni and hydrazine (10 eq) inTHF/Ethanol (1:4), 3 h at room temperature. The reaction mixture arefiltered through celite pad, the volatiles are evaporated and the crudeis used in the next reactions.

Example 1463-Cyanophenyl-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,hydrochloride

To a solution of tert-butyl4-(5-amino-1-benzofuran-7-yl)-piperazine-1-carboxylate (43 mg 0.138mmol) and pyridine (100 μL, 1.24 mmol) was added3-cyanobenzenesulfonylchloride (33.4 mg, 0.166 mmol). After 2 hPS-Trisamin was added and the reaction was stirred overnight. Flashchromatography (DCM/Heptane/MeOH 5:4:1) gave 24.6 mg of a solid. Thecrude product was dissolved in MeOH (2 mL) and HCl/ether 2M (4 mL) wasadded. After 0.5 h the sample was concentrated to afford 19 mg (36%) ofa white solid: ¹HNMR (CD₃OD) δ 8.02-7.88 (m, 3H), 7.72 (d, 1H, J=2.1Hz), 7.76-7.61 (m, 1H), 6.92 (d, 1H, J=2.1 Hz), 6.74 (d, 1H, J=2.1 Hz),6.60 (d, 1H, J=2.1 Hz), 3.52-3.41 (m, 8H); MS (ESI) 381.2 (M+H)⁺; Purity(HPLC, column X) 95%.

Example 1474-Phenoxy-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,hydrochloride

The title compound was prepared according to the method used for thesynthesis of Example 146 (21%) of a white solid: ¹HNMR (CD₃OD) δ 7.73(d, 1H, J=2.1 Hz), 7.69-7.64 (m, 2H), 7.43-7.37 (m, 2H), 7.24-7.17 (m,1H9, 7.04-6.94 (m, 4H), 6.88 (d, 1H, J=2.1 Hz), 6.74 (d, 1H, J=2.1 Hz),6.70 (d, 1H, J=2.1 Hz), 3.53-3.41 (m, 8H); MS (ESI) 450.1 (M+H)⁺; Purity(HPLC, column X) 90%.

Example 1481-Naphthyl-Phenoxy-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,hydrochloride

The title compound was prepared according to the method used for thesynthesis of Example 146 (30%) of a white solid: ¹HNMR (CD₃OD) δ 8.65(d, 1H, J=8.8 Hz), 8.03-7.86 (m, 3H), 7.58-7.49 (m, 3H9, 7.36-7.33 (m,1H), 6.74 (d, 1H, J=2.2 Hz), 6.53 (d, 1H, J=2.2 Hz), 6.30 (d, 1H, J=2.2Hz), 3.52-3.41 (m, 8H); MS (ESI) 408.1 (M+H)⁺; Purity (HPLC) 100%.

Example 149 N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,hydrochloride

The title compound was prepared according to the method used for thesynthesis of Example 146 (33%) of a white solid: ¹HNMR (CD₃OD) δ7.72-7.69 (m, 3H), 7.57-7.51 (m, 1H), 7.47-7.41 (m, 2H), 6.92 (d, 1H,J=2.1 Hz), 6.72 (d, 1H, J=2.1 Hz), 6.58 (d, 1H, J=2.1), 3.49-3.39 (m,8H); MS (ESI) 358.1 (M+H)⁺; Purity (HPLC) 96%.

Example 150 5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonic acid(7-piperazin-1-yl-benzofuran-5-yl)-amide, hydrochloride

The title compound was prepared according to the method used for thesynthesis of Example 146 (9%) of a white solid: ¹HNMR (CD₃OD) δ7.74-7.73 (m, 2H), 7.62 (d, 1H, J=2.2 Hz), 7.38-7.36 (m, 1H), 6.87 (d,1H, J=1.8 Hz), 6.64 (d, 1H, J=2.2 Hz), 6.58 (d, 1H, J=1.8 Hz), 3.36-3.28(m, 8H); MS (ESI) 398.2 (M+H)⁺; Purity (HPLC) 98%.

Example 151N-[7-(4-methylpiperazin-1-yl)-1-benzofuran-5-yl]-benzenesulfonamide,hydrochloride

The title compound was prepared according to the method used for thesynthesis of Example 146 using1-Methyl-4-(5-Nitro-1-benzofuran-7-yl)piperazine (45%) of a white solid:¹HNMR (CD₃OD) δ 7.74-7.283 (m, 6H), 6.82 (d, 1H, J=1.8 Hz), 6.62 (d, 1H,J=2.2 Hz), 6.48 (d, 1H, J=1.8 Hz), 3.82-2.95 (m, 8H), 2.87 (s, 3H); MS(ESI) 372.1 (M+H)⁺; Purity (HPLC, column X) 96%.

Example 1524-Methyl-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,hydrochloride

4-(5-Amino-benzofuran-7-yl)-piperazine-1-carboxylic acid tert-butylester (44 mg, 0.139 mmol) in 3 ml dichloromethane was added to a tubecontaining p-toluenesulfonyl chloride (32 mg, 0.167 mmol) together withpyridine (100 μl, 1.25 mmol) and left on a shaker over weekend. Afterpurification by preparative HPLC, the resulting Boc-material was treatedwith HCl in ether and left on a shaker until the salt had formed. Thesolution was centrifugated and the supernatant was removed. Ether wasadded, then centrifugated and decanted (repeated three times) to removethe excess HCl. The remaining ether was finally evaporated in a SpeedVAcconcentrator to yield 10 mg of title product. HPLC purity=94%, m/z=372.3(M+H). 1H NMR (270 MHz, methanol-d4) δ ppm 2.35 (s, 3H) 3.45 (m, 8H)6.63 (d, J=1.85 Hz, 1H) 6.71 (d, J=2.11 Hz, 1H) 6.88 (d, J=1.85 Hz, 1H)7.25 (m, 2H) 7.58 (m, 2H) 7.71 (d, J=2.11 Hz, 1H).

Example 1533,4-Dimethoxy-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,hydrochloride

HPLC purity=92%, m/z=418.3 (M+H). 1H NMR (270 MHz, methanol-d4) δ ppm3.45 (m, 8H) 3.70 (m, 3H) 3.81 (m, 3H) 6.62 (d, J=1.85 Hz, 1H) 6.73 (d,J=2.38 Hz, 1H) 6.94 (m, 2H) 7.17 (d, J=2.11 Hz, 1H) 7.29 (dd, J=8.44,2.11 Hz, 1H) 7.72 (d, J=2.38 Hz, 1H).

Example 1544-Bromo-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,hydrochloride

HPLC purity=95%, m/z=436.2 (M+H). 1H NMR (270 MHz, methanol-d4) δ ppm3.46 (m, 8H) 6.62 (d, J=1.85 Hz, 1H) 6.74 (d, J=2.38 Hz, 1H) 6.93 (d,J=1.85 Hz, 1H) 7.61 (m, 4H) 7.73 (d, J=2.11 Hz, 1H).

Example 1552,3-Dichloro-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,hydrochloride

HPLC purity=96%, m/z=426.2 (M+H). 1H NMR (270 MHz, methanol-d4) δ ppm3.44 (m, 8H) 6.67 (d, J=1.85 Hz, 1H) 6.72 (d, J=2.11 Hz, 1H) 7.01 (d,J=1.85 Hz, 1H) 7.34 (t, J=8.18 Hz, 1H) 7.70 (m, 2H) 7.94 (dd, J=7.92,1.58 Hz, 1H).

Example 1562,4-Dichloro-5-methyl-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,hydrochloride

HPLC purity=96%, m/z=440.2 (M+H). 1H NMR (270 MHz, methanol-d4) δ ppm2.30 (s, 3H) 3.46 (m, 8H) 6.69 (d, J=1.85 Hz, 1H) 6.73 (d, J=2.11 Hz,1H) 7.01 (d, J=1.85 Hz, 1H) 7.60 (s, 1H) 7.71 (d, J=2.11 Hz, 1H) 7.87(s, 1H).

Example 1574-Methoxy-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,hydrochloride

HPLC purity=93%, m/z=388.3 (M+H). 1H NMR (270 MHz, methanol-d4) δ ppm3.45 (m, 8H) 3.79 (s, 3H) 6.72 (d, J=2.11 Hz, 1H) 6.93 (m, 3H) 7.63 (m,3H) 7.71 (d, J=2.11 Hz, 1H).

Example 1584-Chloro-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,hydrochloride

HPLC purity=97%, m/z=392.3 (M+H). 1H NMR (270 MHz, methanol-d4) δ ppm3.46 (m, 8H) 6.63 (d, J=1.85 Hz, 1H) 6.74 (d, J=2.38 Hz, 1H) 7.47 (m,2H) 7.67 (m, 3H) 7.73 (d, J=2.11 Hz, 1H).

Example 159N-(7-piperazin-1-yl-benzofuran-5-yl)-4-trifluoromethyl-benzenesulfonamide,hydrochloride

HPLC purity=91%, m/z=426.3 (M+H). 1H NMR (270 MHz, methanol-d4) δ ppm3.47 (m, 8H) 6.64 (d, J=1.85 Hz, 1H) 6.74 (d, J=2.11 Hz, 1H) 6.92 (d,J=1.85 Hz, 1H) 7.73 (d, J=2.11 Hz, 1H) 7.84 (m, 4H).

Example 1605-Fluoro-2-methyl-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,hydrochloride

HPLC purity=94%, m/z=390.3 (M+H). 1H NMR (270 MHz, methanol-d4) δ ppm2.57 (m, 3H) 3.46 (m, 8H) 6.63 (m, 1H) 6.74 (d, J=2.11 Hz, 1H) 6.91 (d,J=1.85 Hz, 1H) 7.20 (m, 1H) 7.34 (m, 1H) 7.56 (dd, J=8.71, 2.64 Hz, 1H)7.73 (d, J=2.11 Hz, 1H).

Example 161 5-Chloro-thiophene-2-sulfonic acid(7-piperazin-1-yl-benzofuran-5-yl)-amide, hydrochloride

HPLC purity=94%, m/z=398.3 (M+H). 1H NMR (270. MHz, methanol-d4) δ ppm3.48 (m, 8H) 6.68 (d, J=2.11 Hz, 1H) 6.79 (d, J=2.38 Hz, 1H) 6.97 (d,J=3.96 Hz, 1H) 7.01 (d, J=1.85 Hz, 1H) 7.25 (d, J=3.96 Hz, 1H) 7.76 (d,J=2.38 Hz, 1H).

Biological Tests

The ability of a compound according to the invention to bind a 5-HT₆receptor, and to be pharmaceutically useful, can be determined using invivo and in vitro assays known in the art.

(a) 5-HT₆ Intrinsic Activity Assay

Antagonists to the 5-HT₆ receptor were characterized by measuringinhibition of 5-HT induced increase in cAMP in HEK 293 cells expressingthe human 5-HT₆ receptor (see Boess et al. (1997) Neuropharmacology 36:713-720). Briefly, HEK293/5-HT₆ cells were seeded in polylysine coated96-well plates at a density of 25,000/well and grown in DMEM (Dulbecco'sModified Eagle Medium) (without phenol-red) containing 5% dialyzedFoetal Bovine Serum for 48 h at 37° C. in a 5% CO₂ incubator. The mediumwas then aspirated and replaced by 0.1 ml assay medium (Hanks BalanceSalt Solution containing 20 mM HEPES, 1.5 mM isobutylmethylxanthine and1 mg/ml bovine serum albumin). After addition of test substances, 50 μldissolved in assay medium, the cells were incubated for 10 min at 37° C.in a 5% CO₂ incubator. The medium was again aspirated and the cAMPcontent was determined using a radioactive cAMP kit (Amersham PharmaciaBiotech, BIOTRAK RPA559). The potency of antagonists was quantified bydetermining the concentration that caused 50% inhibition of 5-HT (at[5-HT]=8 times EC₅₀) evoked increase in cAMP, using the formulaK_(i)=IC₅₀/(1+[5HT]/EC₅₀).

The compounds in accordance with the invention have a selective affinityto 5-HT₆ receptors with K_(i) values between 0.5 nM and 5 μM. Thecompounds show good selectivity for 5-HT_(1a), 5-HT_(2a), 5-HT_(2a),5-HT_(2b), 5-HT_(2c).

(b) In Vivo Assay of Reduction of Food Intake

For a review on serotonin and food intake, see Blundell, J. E. andHalford, J. C. G. (1998) Serotonin and Appetite Regulation. Implicationsfor the Pharmacological Treatment of Obesity. CNS Drugs 9:473-495.

Obese (ob/ob) mouse is selected as the primary animal model forscreening as this mutant mouse consumes high amounts of food resultingin a high signal to noise ratio. To further substantiate and compareefficacy data, the effect of the compounds on food consumption is alsostudied in wild type (C57BL/6J) mice. The amount of food consumed during15 hours of infusion of compounds is recorded.

Male mice (obese C57BL/6JBom-Lep^(ob) and lean wild-type C57B1/6JBom;Bomholtsgaard, Denmark) 8-9 weeks with an average body weight of 50 g(obese) and 25 g (lean) are used in all the studies. The animals arehoused singly in cages at 23±1° C., 40-60% humidity and have free accessto water and standard laboratory chow. The 12/12-h light/dark cycle isset to lights off at 5 p.m. The animals are conditioned for at least oneweek before start of study.

The test compounds are dissolved in solvents suitable for each specificcompound such as cyclodextrin, cyclodextrin/methane sulfonic acid,polyethylene glycol/methane sulfonic acid, saline. Fresh solutions aremade for each study. Doses of 30, 50 and 100 mg kg⁻¹ day⁻¹ are used. Thepurity of the test compounds is of analytical grade.

The animals are weighed at the start of the study and randomized basedon body weight. Alzet osmotic minipumps (Model 2001D; infusion rate 8μL/h) are used and loaded essentially as recommended by the Alzettechnical information manual (Alza Scientific Products, 1997; Teeuwesand Yam, 1976). Continuous subcutaneous infusion with 24 hours durationis used. The minipumps are either filled with different concentrationsof test compounds dissolved in vehicle or with only vehicle solution andmaintained in vehicle pre-warmed to 37° C. (approx. 1 h). The minipumpsare implanted subcutaneously in the neck/back region under short actinganesthesia (metofane/enflurane). This surgical procedure lastsapproximately 5 min. It takes about 3 h to reach steady state deliveryof the compound.

The weight of the food pellets are measured at 5 p.m. and at 8 p. m. fortwo days before (baseline) and one day after the implantation of theosmotic minipumps. The weigh-in is performed with a computer assistedMettler Toledo PR 5002 balance. Occasional spillage is corrected for. Atthe end of the study the animals are killed by neck dislocation andtrunk blood sampled for later analysis of plasma drug concentrations.

The plasma sample proteins are precipitated with methanol, centrifugedand the supernatant is transferred to HPLC vials and injected into theliquid chromatography/mass spectrometric system. The mass spectrometeris set for electrospray positive ion mode and Multiple ReactionMonitoring (MRM with the transition m/z 316

221). A linear regression analysis of the standards forced through theorigin is used to calculate the concentrations of the unknown samples.

Food consumption for 15 hours is measured for the three consecutive daysand the percentage of basal level values is derived for each animal fromthe day before and after treatment. The values are expressed as mean±SDand ±SEM from eight animals per dose group. Statistical evaluation isperformed by Kruskal-Wallis one-way ANOVA using the percent basalvalues. If statistical significance is reached at the level of p<0.05,Mann-Whitney U-test for statistical comparison between control andtreatment groups is performed.

The compounds according to the invention show an effect in the range of50-200 mg/kg. TABLE VI In vivo efficacy data on the effect of thecompounds on Food Intake reduction In vivo efficacy - Food intake (15 h)in ob/ob mouse % Inhibition of Food Intake Free plasma concentration inob/ob mice at of the compounds at steady EXAMPLES 50 mg/Kg/day, 15 hstate (Css, u) 48 23.8 0.008 13 24.1 0.035 53 25.7^(a) ND 34 51.4 0.07824 46.2 0.0076 19 69.6 0.150 27 68.9 0.008 30 60.1 0.275 29 71 0.33 1441^(b) 0.23^(a)The effect on Food Intake reported in the table was obtained at thedose of 14.8 mg/kg/d^(b)The effect on Food Intake reported in the table was obtained at thedose of 100 mg/kg/d

1. A compound of the formula V:

or a pharmaceutically acceptable salt thereof, wherein: P is

P and R³ are bound to the same ring and are disposed in meta- orpara-positions relative to each other; R¹ is (a) C₁₋₆ alkyl, (b) C₁₋₆alkoxyalkyl, (c) straight or branched C₁₋₆ hydroxyalkyl, (d) straight orbranched C₁₋₆ alkylhalides; or (e) a group Ar; Ar is (a) phenyl, (b)1-naphthyl, (c) 2-naphthyl, (d) benzyl, (e) cinnamoyl, (f) a 5 to7-membered, optionally aromatic, partially saturated or completelysaturated, heterocyclic ring containing 1 to 4 heteroatoms, selectedfrom oxygen, nitrogen and sulfur, or (g) a bicyclic ring systemcomprising at least one heterocyclic ring according to (f). wherein thegroup Ar is substituted in one or more positions with (a) H, X or Y, or(b) a 5 to 7-membered, optionally aromatic, partially saturated orcompletely saturated, heterocyclic ring each containing 1 to 4heteroatoms selected from oxygen, nitrogen or sulfur; R² is (a) H, (b)C₁₋₆ alkyl, (c) C₁₋₆ alkoxy, (d) straight or branched C₁₋₆ hydroxyalkyl,or (e) straight or branched C₁₋₆ alkylhalides; or R¹ and R² are linkedto form a group (CH₂)₄O; One of R³ is a group

X and Y are independently (a) H, (b) halogen, (c) C₁₋₆ alkyl, (d) —CF₃,(e) hydroxy, (f) C₁₋₆ alkoxy, (g) C₁₋₄ alkenyl; (h) phenyl; (i) phenoxy,(j) benzyloxy, (k) benzoyl, (l) —OCF₃, (m) —CN, (n) straight or branchedC₁₋₆ hydroxyalkyl, (o) straight or branched C₁₋₆ alkylhalides, (p) —NH₂,(q) —NHR⁴, (r) —NR⁴R⁵, (s) —NO₂, (t) —CONR⁴R⁵, (u) —NHSO₂R⁴, (v)—NR⁴COR⁵, (x) —SO₂NR⁴R⁵, (z) —C(═O)R⁴, (aa) —CO₂R⁴, (ab) —S(O)_(n)R⁴;wherein n is 0, 1, 2 or 3; (ac) —S—(C₁₋₆)alkyl, or (ad) —SCF₃; R⁴ and R⁵are independently (a) H, (b) C₁₋₆ alkyl, (c) C₃₋₇ cycloalkyl, or (d) Ar,as defined above for R¹; alternatively, R⁴ and R⁵ are linked to form agroup (CH₂)₂O, (CH₂)₄O or (CH₂)₃₋₅; and R⁶ is (a) H, or (b) straight ofbranched C₁₋₆ alkyl. 2-6. (canceled)
 7. The compound according to claim1, wherein R¹ is (a) C₁₋₆ alkyl, or (e) a group Ar; Ar is (a) phenyl,(b) 1-naphthyl, (c) 2-naphthyl, or (f) a 5 to 7-membered, optionallyaromatic, partially saturated or completely saturated, heterocyclic ringcontaining 1 to 4 heteroatoms, selected from oxygen, nitrogen andsulfur; wherein the group Ar is substituted in one or more positionswith X or Y; wherein X or Y is (a) H, (b) halogen, (c) C₁₋₆ alkyl, (d)—CF₃, (f) C₁₋₆ alkoxy, (g) C₁₋₄ alkenyl; (l) —OCF₃, or (n) straight orbranched C₁₋₆ hydroxyalkyl. R² is (a) H, or (b) C₁₋₃ alkyl, inparticular methyl; or R¹ and R² are linked to form a group (CH₂)₄O; andR³ is

wherein R⁶ is (a) H, or (b) C₁₋₆ alkyl, in particular methyl. 8-10.(canceled)
 11. The compound according to claim 1, wherein the compoundis selected from the group consisting of:4-Methyl-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)benzenesulfonamide,trifluoroacetic acid;4-Bromo-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)benzenesulfonamide,trifluoroacetic acid;N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)naphthalene-1-sulfonamide,trifluoroacetic acid;N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)butane-1-sulfonamide,trifluoroacetic acid;3-Trifluoromethyl-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)benzenesulfonamide,trifluoroacetic acid;3,4-Dimethoxy-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)benzenesulfonamide,trifluoroacetic acid;2,4-Dichloro-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)benzenesulfonamide,trifluoroacetic acid;N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)thiophene-2-sulfonamide,trifluoroacetic acid; and1-Phenyl-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)methanesulfonamide,trifluoroacetic acid.
 12. (canceled)
 13. A process for the preparationof a compound according to claim 1, wherein P is

said method comprising the steps of: (a) nucleophilic aromaticsubstitution of the aromatic halogen atom in 1-chloro-3-nitronaphthaleneor 1-chloro-4-nitronaphthalene with aliphatic or aromatic diamines; (b)reduction of the nitro group in 1-diamine-3-nitronaphthalene or1-diamine-4-nitronaphthalene obtained in step (a) to form1-diamine-3-NH₂-naphthalene or 1-diamine-4-NH₂-naphthalene,respectively; and (c) synthesis of a sulfonamide by reacting1-diamine-3-NH₂-naphthalene or 1-diamine-4-NH₂-naphthalene obtained instep (b) with a suitable sulfonyl chloride.
 14. The process of claim 13,wherein step (a) is by means of Palladium catalyzed nucleophilicsubstitution.
 15. A process for the preparation of a compound accordingto claim 1, wherein P is

said method comprising the steps of: (a) nucleophilic aromaticsubstitution of the trifluoromethanesulfonate group in2-trifluoromethansulfonate-5-nitroquinoline with aliphatic or aromaticdiamines; (b) reduction of the nitro group in 2-diamine-5-nitroquinolineobtained in step (a) to form 2-diamine-5-NH₂-quinoline; and (c)synthesis of a sulfonamide by reacting 2-diamine-5-NH₂-quinolineobtained in step (b) with a suitable sulfonyl chloride.
 16. A processfor the preparation of a compound according to claim 1, wherein P is

said method comprising the steps of: (a) reacting a fluoronaphthaleneand chlorosulfonic acid under acidic conditions, to introduce a sulfonylchloride group in the para position to the carbon having the fluoroatom; (b) reacting the product of step (a) with an aliphatic or aromaticprimary amine to give a sulphonamide; and (c) reaction of the product ofstep (b) with a diamine.
 17. A pharmaceutical formulation containing acompound according to claim 1 as active ingredient, in combination witha pharmaceutically acceptable diluent or carrier.
 18. A method for thetreatment or prophylaxis of obesity, type II diabetes, and/or disordersof the central nervous system, which comprises administering to a mammalin need of such treatment an effective amount of a compound according toclaim
 1. 19. A method for reducing body-weight or reducing food intake,comprising administering to a subject in need thereof an effectiveamount of a compound according to claim
 1. 20. A method for modulating5-HT₆ receptor activity, comprising administering to a subject in needthereof an effective amount of a compound according to claim 1.